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Société Francaise d'Immunologie
May 5, 2019 5:25 AM
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This Review covers new insights into the immune roles of complement. The authors discuss the pathways that link complement signalling with homeostatic and pathological T cell responses and highlight how complement components act intracellularly to shape T cell responses.
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Scooped by
Gilbert C FAURE
February 2, 2019 12:13 PM
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This Review presents our current understanding of C3 glomerulopathy. Smith et al. discuss the histopathological diagnosis and the crucial pathogenic role of complement dysregulation. Genetic and acquired drivers of C3 glomerulopathy, potential biomarkers and available treatments are highlighted.
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Société Francaise d'Immunologie
January 7, 2019 1:31 PM
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Immune evasion strategies employed by intracellular pathogens Pathogens and their hosts co‐evolve, and there are clear signs of selective pressure on host factors such as DNA and RNA sensors on the one hand and pathogen‐encoded immune evasion proteins on the other.65-67 Immunomodulatory proteins and virulence factors are finely tuned to adapt to the host range and life cycle of the pathogen. The precise interplay between host and pathogen factors is often unique, and can differ in different host organisms, cell types and among even closely related pathogens. However, mapping these host–pathogen interactions at a molecular level can provide clues about the importance of host signalling cascades, can help us to understand changes in species specificity and virulence of emerging pathogens, and aid in the design of vaccine vectors. As PRR signalling pathways are being characterized in more molecular detail, the intricate counterstrategies employed by pathogens to evade recognition are also becoming apparent. Some general principles by which intracellular pathogens hide from detection or intercept the cell's signalling cascades are described below. Sequestration of PAMPs Pathogens that reside inside host cells are already sheltered from the immune system to some extent, by avoiding exposure to antibodies or complement components. However, due to the existence of intracellular PRRs, additional camouflage strategies are essential for the establishment of infection. Intracellular bacteria and protozoan parasites often co‐opt vacuoles as a niche for replication, which prevents pathogen‐derived nucleic acids and other PAMPs from being exposed to the cell's PRRs. Hence, detection of intracellular nucleic acids during bacterial infection often requires the presence of bacterial secretion systems. For instance, the type VII secretion system ESX from Mycobacterium tuberculosis is responsible for the exposure of bacterial DNA to cGAS in macrophages, but also secretes virulence factors that interfere with host functions.56, 68 Viruses require greater access to host factors for replication than bacteria, but also try to shield their nucleic acids from detection. Some RNA viruses, including Dengue virus and hepatitis C virus, sequester their genome and replication machinery in membrane‐bound compartments, which function to create locally high concentrations of replication factors, as well as hiding viral RNA genomes from recognition by RIG‐I.69, 70 Human immunodeficiency virus type 1 carries out reverse transcription and replication of its genome inside its capsid, which contains selective pores to allow entry for nucleotides from the host cell, while shielding viral DNA from recognition by cGAS.71 Modification of viral RNA and DNA Many pathogens aim to keep PAMP levels at a minimum: coronaviruses for instance quickly degrade any excessive dsRNA formed during the viral life cycle,72 and Group B streptococcus degrades cyclic di‐AMP using an ectonuclease.73 However, the production of nucleic acid PAMPs cannot be avoided altogether; thus, more sophisticated strategies of camouflage have evolved, so that the pathogen can blend into the cellular environment. As viral RNA polymerases generate RNA species with a 5′ triphosphate moiety, many viruses employ additional strategies to modify their RNA, so that it is not recognized efficiently by RIG‐I. For instance, Picornaviridae, Caliciviridae and Astroviridae covalently attach a protein, Vpg, to the 5′ end of viral RNAs, which prevents RIG‐I‐mediated recognition.15 Processing of the negative‐strand ssRNA genome of members of the Bornaviridae and Bunyaviridae families involves the cleavage of the first nucleotide by a viral endonuclease to generate a monophosphate group at the 5′ end.74 Viruses that transcribe their mRNAs in the nucleus, including the DNA viruses of the Herpesviridae and Papillomaviridae families and retroviruses such as human immunodeficiency virus, co‐opt the cell's own capping machinery to protect the 5′ end of their mRNAs with a 7‐methylguanosine cap, while others, including IAV, use ‘cap snatching’ to remove the capped 5′ ends from cellular mRNAs and incorporate them into viral RNA transcripts.75 Many viruses, including poxviruses and flaviviruses, encode their own capping enzymes that synthesize RNA caps that are indistinguishable from the mammalian cap structure.75 Yellow fever virus in addition recapitulates the 2′ O‐methylation of the first RNA nucleotide next to the cap, which is found in cellular mRNAs and further decreases recognition by RIG‐I.76 Bacteria and protozoa also cap their mRNAs, but not always with 100% efficiency. RNA derived from intracellular bacteria can activate the RNA sensing pathway if it reaches the cytosol, but it remains to be determined whether this is important during infection.77 So far, it is not known whether DNA modifications could prevent recognition by cGAS or other DNA sensors. It has been proposed that IFI16 may be able to distinguish viral DNA from the cell's own genome by recognizing longer (>40 nucleotides) stretches of free DNA,43, 44 and the detection of DNA by cGAS has also been shown to be length‐dependent.78 It remains to be tested whether the assembly of nucleosomes on the genomes of DNA viruses such as herpesviruses and papillomaviruses could be a strategy to limit their detection by intracellular DNA sensors. Degradation and inhibition of host signalling factors All intracellular pathogens encode virulence factors that interfere with the host's signalling cascades. Viral immunomodulatory proteins are usually expressed as immediate early genes, or are even part of the viral particle, so that they are able to inhibit the host's signalling cascades as soon as PAMPs are detected early in infection. Intracellular bacteria employ secretion systems to transport effector proteins through the vacuolar and bacterial membranes into the host cell, whereas protozoans can secrete virulence factors via exosomes or other membrane‐bound vesicles. A vast repertoire of virulence factors that influence the cell's innate immune signalling cascades have been described, particularly in viruses, which often dedicate a large portion of their genome to interfering with the host's innate immune response. Although many viruses encode only a few proteins, these are often multi‐functional and target several key host factors. Large DNA viruses, such as poxviruses and herpesviruses, encode a larger repertoire of dozens of immunomodulatory proteins that interfere with anti‐viral signalling cascades in the cell at multiple points.79, 80 Bacteria and protozoa encode thousands of genes, and so have an even greater capacity to interfere with host functions, but comparatively few immune evasion proteins have been described so far, with many pathogen‐encoded effector proteins still uncharacterized.3, 4, 64 Many pathogens have evolved similar strategies to inhibit the innate immune signalling cascades in the host cell: virulence factors act to either eliminate host signalling factors by degradation, sequester them or block their function in the signalling cascade. As we learn more about the regulation of innate immune signalling cascades that detect pathogens, more examples of counterstrategies employed by pathogens also emerge. Degradation and inhibition of RNA sensors Since the discovery of the intracellular RNA sensing system, many immune evasion proteins that target RLRs or MAVS have been identified (see Fig. 1), mostly in viruses with an RNA genome, for which RIG‐I and/or MDA5 are the key PRRs during infection. Some viral proteases cleave RNA sensors, with several picornaviruses using their 3C protease to cleave RIG‐I, and the 2A protease to cleave MDA5.81-83 The leader protease Lpro from foot‐and‐mouth‐disease virus also cleaves Lpg2, a co‐factor for MDA5 activation.84 Some viruses modify RLRs with K48‐linked poly‐ubiquitin chains, diverting the RNA sensors for degradation by the cell's proteasome. Toscana virus non‐structural proteins and the rotavirus NSP1 protein cause the degradation of RIG‐I,85, 86 whereas West Nile virus NS1 targets both RIG‐I and MDA5.87 RIG‐I mRNA expression and translation can also be inhibited during viral infection: for instance, EBV expresses the virus‐encoded microRNA miR‐BART6‐3p, which targets RIG‐I mRNA,88 and hepatitis B virus induces the cellular microRNA miR146a, which inhibits RIG‐I expression.89 Even under conditions where the expression of RIG‐I and MDA5 is intact, the RNA sensors can be prevented from carrying out their signalling function by viral proteins that bind to them. The HSV‐1 protein UL37 interacts with RIG‐I and causes the de‐amidation of its helicase domain, which renders RIG‐I unable to sense RNA ligands.90 Another HSV‐1 protein, US11 inhibits RNA sensing by associating with the dsRNA binding protein PACT, which potentiates RNA‐induced responses.91, 92 PACT is also targeted by Influenza A virus NS1, the VP35 protein from Ebola virus and the 4a protein from Middle East respiratory syndrome coronavirus.93-95 Many of the PACT‐interacting proteins also bind dsRNA, so they probably shield the viral RNA from detection while at the same time inactivating PACT and RNA sensors. The activity of RIG‐I and MDA5 is tightly regulated in the cell: In the absence of infection, the CARD of the RNA sensors are kept in a phosphorylated state, and activation involves their dephosphorylation catalysed by protein phosphatase 1.96 RIG‐I activity is further enhanced by the assembly of K63‐linked poly‐ubiquitin chains catalysed by the E3 ubiquitin ligases tripartite motif containing 25 (TRIM25) and Riplet, which release RIG‐I from its autoinhibited state.97, 98 Given the importance of these post‐translational modifications, it is not surprising that many viruses have evolved ways of inhibiting these regulatory mechanisms. For instance, measles virus uses an elaborate signalling strategy involving the activation of the C‐type lectin DC‐SIGN to inhibit protein phosphatase 1, thus keeping the RLRs phosphorylated and inactive.99 The E3 ubiquitin ligase Riplet is inhibited by the multifunctional IAV NS1 protein100 and is cleaved by the NS3/4A protease from hepatitis C virus.101 Multiple viruses also inhibit TRIM25, including again IAV NS1, the SARS coronavirus N protein, the V protein from various paramyxoviruses, the large tegument protein BPLF1 from EBV and the E6 protein from human papillomavirus 16.102-107 The subgenomic flavivirus RNA from Dengue virus can also bind and inactivate TRIM25 in an RNA sequence‐specific manner.108 RIG‐I ubiquitylation by TRIM25 is also inhibited by the bacterial quorum sensing molecule cyclo(Phe‐Pro) from the opportunistic pathogen Vibrio vulnificus. Cyclo(Phe‐Pro) specifically binds to RIG‐I and prevents it from being ubiquitylated by TRIM25,109 possibly providing a link between bacterial infection and susceptibility to co‐infection with viruses. A multitude of viral immunomodulators prevent RIG‐I and MDA5 from interacting with its adaptor protein MAVS, so blocking the nucleation event that allows MAVS to form higher‐order signalling assemblies. Dengue virus NS3 binds 14‐3‐3ε to prevent the translocation of RIG‐I to MAVS.110 The interaction between RLRs and MAVS is also disrupted by the picornavirus 3Cpro proteases, the Z and N proteins of some arenaviruses, NS2 from respiratory syncytial virus, NS1 from IAV, NSP1 from rotavirus and US11 from HSV‐1.16, 86, 111-114 MAVS is also targeted directly by many viruses. MAVS‐interacting proteins include the metapneumovirus protein M2‐2,115 the NS4A proteins of Zika and Dengue viruses,116, 117 viral IRF1 from human herpesvirus 8118 and ORF9b from SARS coronavirus.119 MAVS is also diverted for proteasome‐mediated degradation by the hepatitis B virus X protein,120 and is cleaved by the hepatitis C virus protease NS3/4A, which releases it from the mitochondria and other intracellular membranes to disrupt signalling.121-124 The US9 protein from HSV‐1 causes MAVS to leak from the mitochondria by disrupting the mitochondrial membrane potential,125 and the IAV protein PB1‐F2 decreases mitochondrial membrane potential causing mitochondrial fragmentation.126, 127 Disrupting mitochondrial physiology is a common mechanism to block MAVS signalling. Infection with Dengue and Zika viruses causes mitochondrial elongation, which also blocks MAVS function.128 The sustained interferon production caused by MAVS signalling from the peroxisomes is inhibited by the MIA protein from human cytomegalovirus (hCMV) and the VP16 protein from HSV‐1.118, 129, 130 Although there are abundant examples of inhibition of RNA sensing by pathogens, and in particular viruses, there is one instance where a pathogen actually enhances signalling by RIG‐I and MDA5. The food‐borne pathogen Salmonella typhimurium uses its effector protein SopA, an E3 ubiquitin ligase, to ubiquitylate the host proteins TRIM56 and TRIM65, which in turn promote RIG‐I and MDA5 signalling.131, 132 This is an example of subversion, rather than evasion, of the interferon response, in line with the observation that the production of type I interferons can be advantageous to the pathogen, rather than the host, during some bacterial infections.64 Degradation and inhibition of DNA sensors Even though the cGAS/STING DNA sensing pathway was only discovered relatively recently, several viral and bacterial virulence factors that target this pathway have already been discovered, see Fig. 2. The nuclear DNA viruses hCMV, HSV‐1 and Kaposi's sarcoma‐associated herpesvirus all target several key DNA sensing factors to prevent the detection of their genomic DNA. HSV‐1 uses its ICP27 protein to inhibit STING.133 In addition, the E3 ubiquitin ligase ICP0 causes the degradation of IFI16 protein, and the virion host shutoff protein UL41 promotes the turnover of the mRNAs encoding IFI16 and cGAS.42, 134, 135 In addition, the HSV‐1 virion protein VP22 interacts with cGAS and inhibits its enzymatic activity136 and also interacts with AIM2 and blocks its oligomerization.137 HSV‐1 tegument protein UL37, which targets and deamidates RIG‐I, also deamidates cGAS, impairing cGAMP synthesis.138 The deployment of different virulence factors to target several components of the DNA sensing pathway may be necessary to block the pathway more efficiently, and/or to inhibit some non‐overlapping functions of cGAS and IFI16 which have been observed during herpesvirus infection.139 Analogously, several different hCMV proteins inhibit DNA sensing: pUL31 binds to cGAS and dissociates it from DNA,140 pUL83 inhibits both cGAS and IFI16,141-143 pUL82 inhibits STING translocation,144 IE2 causes STING degradation,145 and US9 inactivates both MAVS and STING.125 Furthermore, pUL83 binds AIM2 and facilitates the degradation of AIM2‐driven inflammasomes.146 A similar multi‐pronged approach has also been observed for the gammaherpesvirus Kaposi's sarcoma‐associated herpesvirus.147-150 STING is also inhibited by oncoproteins from the nuclear DNA viruses human adenovirus and human papillomavirus,151 and by vaccinia virus, a DNA virus that resides in the cytosol.152 Vaccinia virus also inhibits DNA‐PK, using its virulence factor C16 to bind the Ku70/Ku80 subunits of the DNA‐PK complex.153 The viral inhibitor of RIP activation (vIRA) from mouse CMV targets another proposed DNA sensor, DAI, to prevent the induction of programmed necrosis upon viral infection.154 Surprisingly, not only DNA viruses but also some RNA viruses have been found to antagonise STING – even though they do not produce DNA or cyclic dinucleotides during their replication cycle. It has been reported that STING can function in a cGAS‐independent manner during the detection of viral membrane fusion, for instance during infection with IAV.155 This non‐canonical STING signalling pathway is antagonized by the IAV fusion peptide.156 Flaviviruses, enveloped viruses with a positive‐stranded ssRNA genome, also inhibit STING‐dependent DNA sensing. Viral NS2B proteases encoded by Dengue virus, Zika virus, West Nile virus and Japanese encephalitis virus cleave human STING protein, but not its mouse orthologue.157, 158 The dengue virus NS2B co‐factor also targets cGAS for degradation.55 This prevents the activation of an innate immune response after the release of mitochondrial DNA, which occurs during Dengue virus infection,55, 159 highlighting the breadth of pathogen classes that can be detected directly or indirectly by the DNA sensing pathway (Fig. 2). While the production of type I interferons is not always an effective strategy to limit bacterial infections, the activation of STING by bacterial DNA or cyclic dinucleotides can also promote autophagy to clear bacteria from the infected cells. For this reason, some intracellular bacteria also inhibit STING.62 For instance, the Shigella effector protein IpaJ inhibits STING translocation from the endoplasmic reticulum to endoplasmic reticulum–Golgi intermediate compartment,38 and the Yersinia YopJ protein also blocks STING trafficking and causes its de‐ubiquitylation.160 Mycobacterium tuberculosis secretes the cyclic di‐nucleotide phosphodiesterase CdnP (also known as Rv2837c), which degrades cGAMP and bacterial cyclic dinucleotides, thus inhibiting both DNA‐ and cyclic‐dinucleotide‐induced STING activation.161 Group A streptococcus, Streptococcus pyogenes, subverts, rather than evades, STING signalling: it uses its M protein to activate STING, resulting in the production of the anti‐inflammatory cytokine interleukin‐10 downstream of type I interferon signalling.162 In this way, the bacterium exploits the reciprocal antagonism between the interferon response and inflammation, and shapes the immune response to favour the pathogen, rather than the host.
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Suggested by
Société Francaise d'Immunologie
December 11, 2018 3:30 AM
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Summary The role of the host extracellular matrix (ECM) in infection tends to be neglected. However, the complex interactions between invading pathogens, host tissues and immune cells occur in the context of the ECM. On the pathogen side, a variety of surface and secreted molecules, including microbial surface components recognizing adhesive matrix molecules and tissue‐degrading enzymes, are employed that interact with different ECM proteins to effectively establish an infection at specific sites. Microbial pathogens can also hijack or misuse host proteolytic systems to modify the ECM, evade immune responses or process biologically active molecules such as cell surface receptors and cytokines that direct cell behaviour and immune defence. On the host side, the ECM composition and three‐dimensional ultrastructure undergo significant modifications, which have a profound impact on the specific signals that the ECM conveys to immune cells at the forefront of infection. Unexpectedly, activated immune cells participate in the remodelling of the local ECM by synthesizing ECM glycoproteins, proteoglycans and collagen molecules. The close interplay between the ECM and the innate immune response to microbial pathogens ultimately affects the outcome of infection. This review explores and discusses recent data that implicate an active role for the ECM in the immune response to infection, encompassing antimicrobial activities, microbial recognition, macrophage activation, phagocytosis, leucocyte population balance, and transcriptional and post‐transcriptional regulation of inflammatory networks, and may foster novel antimicrobial approaches. Introduction To successfully establish an infectious disease, most pathogenic bacteria adhere to the host, invade underlying tissues, and multiply and grow while evading or overcoming host immune defences.1 The underlying host–pathogen interactions are remarkably specific and involve a variety of substrates within the host. The interactions of pathogens with eukaryotic cells have been intensively studied in microbiology, immunology, cell biology, genetics and ecology research. Less attention has been given to the host extracellular matrix (ECM). However, the individual components of the ECM are substrates that pathogens can directly bind to or degrade, facilitating adhesion and penetration into the host; evidence for this started to accumulate 40 years ago.2, 3 Furthermore, the ECM is a fundamental component of the host cellular microenvironment where most of the events leading to infection, disease and tissue repair take place and is also a reservoir of diverse and tissue‐specific signals that feed into immunological pathways.4, 5 Recently, evidence has emerged that the ECM conveys specific signals to cells, thereby modulating essential immune functions, immune cell migration into and within infected tissues, and immune cell activation, proliferation and differentiation. Moreover, the ECM composition undergoes significant alterations during infection and, notably, specific immune cell types appear to contribute to that. Hence, regulatory circuits closely link the ECM and the immune system. Important questions to emerge from these studies include (i) does the ECM play an active role in infection rather than simply providing a scaffold for bacterial adhesion or being a barrier to breach; (ii) which ECM–pathogen interactions significantly impact the ability of pathogens to colonize and invade host tissues, and/or bypass host defences, and influence how host cells respond to pathogens; and (iii) can we interfere with these interactions to develop new antimicrobial strategies or improve existing ones. Here, we briefly review the ECM and its interactions with microbial pathogens, and discuss the evidence for a direct implication of the ECM in the immune response to infection. The ECM: an immunological perspective Most infections and the resulting immune responses are tissue‐specific. Each tissue has distinct ECM signatures that arise from complex and dynamic combinations of up to ~ 300 different proteins in varying concentrations and geometries within the three‐dimensional extracellular space. This ever increasing number of proteins that contribute to matrices (the ‘matrisome’) include approximately 43 collagen subunits, 36 proteoglycans and 200 glycoproteins.6 ECM molecular multiplicity and complexity are amplified by post‐translational modifications, which can unveil cryptic epitopes or generate new ones capable of triggering immune reactions, and alternative splicing, which generates several isoforms with distinct functions.7, 8 For instance, laminin α4 and α5 isoforms in basement membranes contribute to immune cell subtype selectivity during leucocyte recruitment to sites of inflammation.9, 10 Interstitial ECMs, loose fibril‐like matrices that fill the tissue stroma, and basement membranes, laminar sheets that anchor cell layers to underlying tissues, are basic forms of ECM. Additionally, specialized reticular fibre networks combining features of these two ECM structures are found in secondary lymphoid organs.11, 12 The ECM is a highly dynamic yet strictly regulated tissue component. Its composition and normal function are determined and maintained by a fine balance between ECM synthesis, orchestrated by cytokines such as transforming growth factor‐β (TGF‐β), and turnover, accomplished by matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs), whose activity is controlled by tissue inhibitors of metalloproteinases (TIMPs).13 During injury and infection, these enzymes are produced by activated immune cells such as monocytes/macrophages and promote immune cell migration into sites of infection and tissue damage, and affect their ability to mount inflammatory responses.14 The central dogma of matrix biology describes how the ECM provides structural support for cells and contributes to the unique structure of a tissue. However, this is only one function of the ECM. Host immune responses are carried out in the context of the ECM, so when immune cells contact the ECM, they receive vital instructions for their survival, proliferation, differentiation and activation, in addition to support for adhesion and guidance for migration. Several mechanisms are responsible for the communication between the ECM and cells. One such mechanism is signalling through cell surface adhesion molecules and receptors, including integrins and discoidin‐domain receptors (reviewed in refs 15, 16). Others involve binding, storage, activation and release of secreted molecules with potent immunomodulatory activity, including cytokines, chemokines and growth factors.17, 18 For instance, TGF‐β has been shown in vitro and in vivo to affect activation, proliferation and differentiation of most immune cell types, modulating nearly all stages of the immune response.19 Moreover, bioactive ECM fragments generated by tissue destruction (e.g. hyaluronan and heparan sulphate oligosaccharides) and ECM molecules whose expression is specifically induced upon tissue injury (e.g. fibronectin isoforms containing extra domain A, versican and biglycan) promote inflammation by inducing pro‐inflammatory gene expression or exhibiting chemoattractant properties (reviewed in refs 20, 21). These molecules form a class of endogenous damage‐associated molecular patterns,22 which, by activating pattern recognition receptors (PRRs) such as toll‐like receptors (TLRs) in immune cells (e.g. macrophages and dendritic cells) and non‐immune cells (e.g. fibroblasts and epithelial cells) alert the immune system to tissue damage and infection, which initiates not only pathogen clearance, but also tissue repair.23 Hence, the ECM and the immune system are intertwined: signals from the ECM help to coordinate immune responses and, in turn, immune cells promote ECM repair and regeneration through the release of cytokines such as tumour necrosis factor (TNF), interferon‐γ (IFN‐γ) and TGF‐β, which regulate the expression of many ECM molecules. ECM–pathogen interactions A tale of adhesion and colonization of the host Tissue adherence represents the first essential mechanism that bacteria adopt to colonize the host. Failure to do so results in the organism being removed by physiological cleansing systems at sites of entry. The surface of host cells and the ECM are negatively charged and microbes employ a number of physico‐chemical forces to overcome these repulsive forces and establish interactions between a microbial ligand or ‘adhesin’ and a complementary molecule or ‘receptor’ on the host tissue. These interactions are highly specific, contributing to tissue tropism, species specificity and genetic specificity within a species. Bacterial adhesins are components of capsules, cell walls, pili or fimbriae, and those that bind to ECM components are called ‘microbial surface components recognizing adhesive matrix molecules’. Host receptors are usually glycoproteins found on the cell membrane and ECM components.24 The binding of microbial pathogens to specific ECM proteins has been extensively reviewed elsewhere1, 3, 25, 26 and will be briefly discussed here. The first report of a host ECM–pathogen interaction was published in 1978 by Kuusela et al.2 who studied the binding of Staphylococcus aureus to fibronectin and, a few years later, revealed two separate binding sites on fibronectin, in the N‐terminus and C‐terminus, respectively.27 Other groups further characterized the interaction of this ubiquitous and promiscuous ECM glycoprotein with Staphylococcus aureus and Streptococcus pyogenes, which has a remarkably large number of fibronectin binding adhesins.28-33 Several other ECM proteins such as laminin, collagen, heparan and chondroitin sulphate, vitronectin, thrombospondin, elastin, bone sialoprotein and tenascin‐C, have since been implicated in specific interactions with pathogenic bacteria26, 34 (Table 1). ECM molecule Pathogen Adhesin Effect of interaction Disease References Fibronectin Enterohaemorrhagic Escherichia coli O157:H7 Lpf fimbriae (LpfA1 major subunit) Colonization of GI tract Acute diarrhoea; bloody diarrhoea; haemolytic uraemic syndrome 130 Streptococcus pyogenes (group A streptococci, GAS) Protein F1 (functional upstream domain) Fibronectin links F1 to integrin receptors, helping bacterial uptake Tonsillopharyngitis; necrotizing fasciitis; myositis; streptococcal toxic shock syndrome 131-133 Protein F2 (C‐terminal domains) Host cell adhesion and internalization 33 SfbII (C‐terminal domain) Host cell adhesion and internalization 134 Fba Host cell adhesion and internalization 31* Staphylococcus aureus MntC Mucosal colonization Nosocomial infections, septicaemia, osteomyelitis, endocarditis, etc. 135 Salmonella typhimurium MisL (N‐terminal non‐conserved region) Intestinal colonization Gastroenteritis 136* ShdA 137 Plasma fibronectin Borrelia burgdorferi BBK32 Binding to fibronectin 13FnIII repeat module and intestinal colonization Lyme disease 35 Fibronectin N‐terminal proteolytic fragments (30 and 70 kDa) Streptococcus pyogenes Protein F2(C‐terminal domains) Fibronectin polymerization and colonization of vascular surfaces Tonsillopharyngitis; necrotizing fasciitis; myositis; streptococcal toxic shock syndrome 33 130 Laminin EnterohaemorrhagicEscherichia coli O157:H7 Lpf fimbriae (LpfA1 major subunit) Eukaryotic cell adhesion and internalization Acute diarrhoea; bloody diarrhoea; haemolytic uraemic syndrome 130 EnterohaemorrhagicEscherichia coli O157:H7 Lpf fimbriae (LpfA1 major subunit) Colonization of GI tract Acute diarrhoea; bloody diarrhoea; haemolytic uraemic syndrome 135 Staphylococcus aureus MntC Colonization of GI tract Nosocomial infections, septicaemia, osteomyelitis, endocarditis, etc. 138 Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Mucosal colonization Infective endocarditis 139 Collagen I Borrelia burgdorferi ErpX Adhesion and invasion of endothelial cells Lyme disease 138 Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Long‐term host tissue colonization Infective endocarditis 137 Salmonella typhimurium ShdA Adhesion and invasion of endothelial cells Gastroenteritis 140* Collagen II Enterococcus faecium Pilus subunits EmpA and EmpB Intestinal colonization and persistence UTIs, bacteraemia, and infective endocarditis 138 Collagen IV Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Adherence to host tissue and biofilm formation Infective endocarditis 130 EnterohaemorrhagicEscherichia coli O157:H7 Lpf fimbriae (LpfA1 major subunit) Adhesion and invasion of endothelial cells Acute diarrhoea; bloody diarrhoea; haemolytic uraemic syndrome 135 Staphylococcus aureus MntC 138 Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Colonization of GI tract Nosocomial infections, septicaemia, osteomyelitis, endocarditis, etc. 136* Collagen V Salmonella typhimurium MisL (N‐terminal non‐conserved region) Mucosal colonization Infective endocarditis 141 Collagen VI Enterococcus faecium EcbA Adhesion and invasion of endothelial cells Gastroenteritis 142* Tenascin‐C Legionella pneumophila Mip Intestinal colonization UTIs, bacteraemia, and infective endocarditis 138 Vitronectin Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Host tissue adhesion and biofilm formation Legionellosis 138 Streptococcus gallolyticus (gallolyticus endocarditis isolates) FimB, gtf and pilB Adhesion to lung tissue and bacterial dissemination Infective endocarditis 143* Yersinia enterocolitica YadA Adhesion and invasion of endothelial cells Infective endocarditis 46 Thrombospondin Trypanosoma cruzi TcCRT Adhesion and invasion of endothelial cells Enteric and systemic diseases 144* Decorin Borrelia burgdorferi DbpA and DbpB Adhesion to host cells and tissue; improved bacterial survival Chagas disease 141 Nidogen 1 and 2 Enterococcus faecium SgrA Enhancement of cellular infection Lyme disease 145, 146 Soluble and immobilized fibrinogen(α‐ and β‐chains) Staphylococcus aureus ClfA, ClfB Specific localization to decorin‐rich niches in the tunica adventitia and myocardial connective tissue; persistence of infection UTIs, bacteraemia, and infective endocarditis Host tissue adhesion and biofilm formation Nosocomial infections, septicaemia, osteomyelitis, endocarditis, etc. Colonization of biomaterial implants; bacterial spread GI, gastrointestinal; UTI, urinary tract infection; LpfAI, long polar fimbrae subunit 1; SfbII, fibronectin surface binding protein II; Fba, fibronectin binding protein; MntC, manganese transport protein C; MisL, autotransport protein MisL; FimB, type I fimbriae regulatory protein FimB; gtf, glucosyltransferase; pilB, type 4 fimbrial assembly protein; EcbA, E. faecium collagen binding protein A; MIP, macrophage infectivity potentiator; YadA, adhesin YadA; TcCRT, Trypanosoma cruzi calreticulin; DdpA/ DdpB, decorin binding protein A and B; SgrA, serine‐glutamate repeat containing protein A; ClfA/ClfB, clumping factor A and B. Early studies were mostly limited by the use of binding assays, involving bacterial cells or recombinant adhesins and ECM molecules, and inhibition experiments to demonstrate these interactions. Cutting‐edge technologies, including live cell imaging and particle‐tracking methods, have now started to reveal the implications of these interactions in pathogenesis. For example, Niddam et al. showed that the Lyme disease spirochaete Borrelia burgdorferi exploits fibronectin to interact with vascular surfaces under physiological shear stress. Specifically, it recruits and induces polymerization of soluble plasma fibronectin that strengthens and stabilizes bacterial interactions with endothelia by a catch–bond mechanism.35 Breaking down barriers to invade the host Having colonized the host, most pathogens need to invade tissues to cause disease. This requires the breakdown of primary and/or secondary defences of the host, involving the crossing of basement membranes and interstitial matrices. Pathogens have developed distinct ways to modify the ECM.1, 36 They can directly degrade ECM components using ‘invasins’ or bacterial tissue‐degrading enzymes such as hyaluronidases and collagenases, causing local tissue damage. Specific examples of these interactions are reported in Table 2 and reviewed elsewhere.26, 36 Degradation of the ECM not only facilitates the spread of pathogens, but can also favour tissue necrosis, bacterial toxin diffusion and host cell adhesion, migration and survival. Pathogens can also indirectly modify the ECM by altering the synthesis and turnover of ECM components by host cells in response to their presence (discussed later in this review). Moreover, pathogens can hijack or misuse host proteolytic systems. For instance, Staphylococcus aureus,37 Haemophilus influenzae38 and Pseudomonas aeruginosa,39 among other common pathogenic bacteria, manipulate the plasminogen–plasmin system thereby degrading laminin and fibronectin and activating MMP zymogens that not only degrade all types of ECM proteins, but also process many biologically active molecules (e.g. cell surface receptors and cytokines) that direct cell behaviour and host defence. ECM molecule Pathogen Microbial enzyme Effect of ECM cleavage Disease References Laminin Psedomonas aeruginosa Elastase; alkaline protease Tissue invasion and necrosis Necrotizing pneumonia, septic shock, UTI, skin and soft‐tissue infections 147 # Clostridium difficile Cwp84 Tissue integrity loss; facilitation of toxin diffusion Pseudomembranous colitis and nosocomial diarrhoea 148 Collagen I Porphyromonas gingivalis Gingipains in P. gingivalis supernatant Tissue degradation Periodontal disease 149 Vibrio parahaemolyticus Metalloprotease VppC Tissue damage Acute gastroenteritis 150 Collagen I, II, III, IV, V and VI Clostridium histolyticum Class I and II collagenases (ColG, ColH) Necrotic tissue degradation; promote keratinocyte migration Gas gangrene, infective endocarditis 151, 152 Collagen IV Streptococcus gordonii Serine protease Basement membrane breakdown Infective endocarditis 153 Fibronectin Clostridium difficile Cwp84 Tissue integrity loss; facilitation of toxin diffusion Pseudomembranous colitis and nosocomial diarrhoea 148 Porphyromonas gingivalis Gingipains in P. gingivalis supernatant; HRgpA and RgpB gingipains Cleavage and inactivation of cell‐binding region of fibronectin; gingival fibroblast detachment and death; tissue destruction Periodontal disease 149, 154 # Vitronectin Clostridium difficile Cwp84 Tissue integrity loss; facilitation of toxin diffusion Pseudomembranous colitis and nosocomial diarrhoea 148 Tenascin‐C (large isoforms) Porphyromonas gingivalis HRgpA, RgpB and Kgp gingipains Enhanced anti‐adhesive activity of tenascin‐C; gingival fibroblasts detachment, apoptosis and tissue destruction Periodontal disease 154 # Cwp84, putative cell surface‐associated cysteine protease; HRgpA and RgpB, arginine‐gingipains; Kgp, lysine‐gingipains; UTI, urinary tract infection. Strategies to evade the host immune response? Although numerous pathogens undoubtedly exploit ECM components and ECM‐associated molecules to adhere to and degrade tissues for efficient host colonization and invasion, it is not always clear whether pathogens interact with these ECM molecules also to evade immune responses. For instance, Borrelia burgdorferi can avoid antibody‐mediated clearance and this may be partly explained by its specific interaction with decorin.36 The Haemophilus influenzae surface protein E binds to plasminogen, which is converted to plasmin, and uses plasmin for complement evasion and innate immune escape.37 Several other pathogenic bacteria take advantage of the host plasminogen system to facilitate their own spread and invasion through tissues.40, 41 Notably, Helicobacter pylori benefits from the complement regulatory property and the plasminogen‐binding ability of vitronectin to protect itself from innate immune responses.42 Furthermore, Group B streptococci and other Gram‐positive bacteria secrete hyaluronidases, whose activity allows immune evasion besides tissue invasion. Specifically, their hyaluronidases process pro‐inflammatory hyaluronan fragments into disaccharides, which block TLR2/4 signalling triggered by host‐derived hyaluronan fragments and pathogenic ligands, including lipopolysaccharide (LPS), thereby evading immune detection.43 Altered ECM dynamics in infection and its implications The ECM undergoes significant alterations upon infection that promote or inhibit the establishment of infection and the host response to it. Below is an overview of the changes in ECM synthesis, degradation and post‐translational modification during infection and a discussion of their implications in pathogenesis. ECM synthesis and deposition Signal transduction pathways activated upon pathogen entry and recognition, and by mediators of inflammation and tissue repair during infection all contribute to ECM synthesis and deposition. This involves structural ECM proteins (e.g. collagens, laminins and proteoglycans) as well as non‐structural ECM components termed ‘matricellular proteins’, which are normally absent or scarcely expressed in healthy tissues (e.g. osteopontin, thrombospondins, galectins, tenascins). For instance, rhinovirus activates TLR3 and TLR7/8 signalling in airway smooth muscle cells, which leads to increased deposition of fibronectin, perlecan and collagen IV, contributing to airway remodelling and facilitating the migration of airway smooth muscle cells to the infection site.44 Interleukin‐33 (IL‐33) signalling induced by Staphylococcus aureus enhances fibronectin and collagen IIIa expression and deposition, accelerating wound repair.45 Systems biology approaches elucidating the ECM interactome network regulated by Trypanosoma cruzi and its gp83 ligand, which mediates trypanosome attachment and entry, have shown that activation of gp83 receptors in the cell via extracellular signal‐regulated kinase 1/2 results in up‐regulation of laminin γ1 and thrombospondin expression to facilitate trypomastigote recruitment, enhancing cellular infection.46 In mice, Citrobacter rodentium infection induces osteopontin and fibronectin expression through integrin‐linked kinase activation, facilitating bacterial colonization of the intestine.47 High expression levels of osteopontin have also been shown to be induced in murine acute and chronic coxsackievirus B3‐myocarditis together with those of MMP‐3, TIMP1, urokinase‐type plasminogen activator and TGF‐β1 and, in turn, procollagen‐1α mRNA expression and fibrosis. Accordingly, osteopontin‐null mice are protected from viral myocarditis, and inhibition of osteopontin transcription by vitamin D decreases cardiac fibrosis in wild‐type animals.48 Viral myocarditis also results in up‐regulation of tenascin‐C before immune cell infiltration occurs and until scar tissue is formed.49 Elevated tenascin‐C levels have also been reported in patients with sepsis, parapneumonic infection, tuberculosis and Staphylococcus aureus infection.50-54 Furthermore, the lungs of mice infected with Gram‐negative bacteria show accumulation of versican, a chondroitin sulphate proteoglycan with multiple cytokine, chemokine, adhesion molecule and growth factor‐binding domains, that is implicated in the innate immune response.55 Similarly, when primary human lung fibroblasts are treated with the viral mimetic Poly I:C, they deposit a higher‐order structured ECM, rich in versican and hyaluronan, to which T cells avidly adhere and cease migration, an effect reversed by hyaluronidase treatment or versican antibody during matrix formation.56 Importantly, besides expression levels, infection can also alter the spatial distribution of ECM components as it emerges from influenza‐infected lungs, which show distinct regions that are enriched with either fibronectin or collagen.57 Hence, specific infectious diseases seem to generate distinct compositional changes of the ECM, inevitably influencing its biophysical structure and presentation of bioactive compounds that impact bacterial colonization and invasion, immune cell response and tissue repair. ECM degradation The catabolic machinery that breaks down and remodels the ECM is also altered upon infection, affecting the supportive, barrier and biological functions of the ECM. Tissue degrading enzymes such as MMPs play a crucial role in regulating immune cell recruitment: they cleave the basement membrane ECM; expose cryptic pro‐migratory sites of ECM components (e.g. γ2 chain of laminin 5); target non‐ECM proteins such as adhesion molecules (e.g. E‐cadherin); activate, deactivate or regulate the bioavailability of chemokines (e.g. monocyte cheomattractant protein‐1 and IL‐8) and cytokines (e.g. IL‐1β and TNF‐α); and shed cell surface receptors associated with cell migration (e.g. CD44), modulating inflammation (reviewed in refs 58-60). With the exception of neutrophils, tissue‐degrading enzymes are not stored, but require de novo synthesis that is strictly regulated and can be induced by pro‐inflammatory cytokines (e.g. TNF‐α and IL‐1) and also by bacterial products (e.g. LPS and chlamydial heat‐shock proteins).61 Several pathogens, including Mycobacterium bovis, Mycobacterium tuberculosis, Streptococcus pyogenes and Helicobacter pylori, induce expression and activity of a number of MMPs, including MMP‐1, MMP‐2, MMP‐7, MMP‐9 and MMP‐13.62-64 In particular, the extensive production of MMP‐2 and MMP‐9 during mycobacterial infection is regulated by macrophage‐derived and T‐cell‐derived cytokines and causes ECM breakdown. This may be necessary for cell recruitment and granuloma formation, both protective immune responses to mycobacteria. However, dysregulation of MMP production at late stages of the infection could contribute to tissue damage and, by compromising tissue integrity, may facilitate bacterial dissemination and persistence of infection.62 Systemic Escherichia coli infection, acute Lyme neuroborreliosis and pneumococcal meningitis can all lead to secretion of high amounts of MMP‐9. In meningitis, MMP‐9 has been suggested to contribute to blood–brain barrier destruction and neuronal injury.65-67 Similarly, gastrin‐dependent induction of MMP‐7 upon Helicobacter pylori infection has been implicated in the development of gastric cancer through the release of heparin‐binding epidermal growth factor.64 Chlamydia trachomatis, which causes trachoma and blindness, up‐regulates MMP‐7, MMP‐9, MMP‐12 and TIMP‐1 expression, while it down‐regulates MMP‐10 and SPARC (secreted protein, acidic, cysteine‐rich)‐like 1, a matricellular protein that regulates decorin production and collagen assembly.68 In this study the expression pattern of these ECM‐modifying enzymes was correlated with the clinical scarring grade and inflammation. Interestingly, a dual function has been shown for MMP‐12 in viral myocarditis caused by coxsackievirus type B3. While intracellular MMP‐12 causes IFN‐α secretion and host protection, extracellular MMP‐12 cleaves the IFN‐α receptor 2 binding site of IFN‐α, preventing an uncontrolled immune response.69 In the same model of viral myocarditis, MMP‐9 exerts a protective role by inactivating IFN‐β/γ. Indeed, MMP‐9‐null mice display higher viral load, infiltration of CD3+ cells and tissue damage.70 However, murine MMP‐9 can also enhance susceptibility to infection and increase morbidity and mortality. This is the case in Francisella tularensis pulmonary infection where MMP‐9 generates pro‐inflammatory ECM‐derived peptides (i.e. Pro‐Gly‐Pro peptide from collagen I), enhancing neutrophil infiltration to lungs.71 In addition to inducing MMP expression, pathogens can also activate pro‐MMPs by secreting their own activating enzymes, as in the case of Pseudomonas aeruginosa, which activates pro‐MMP‐2 using LasB, a thermolysin‐like metalloprotease.39 The role of dysregulated tissue‐degrading enzymes, individually or in combination, is not well understood in every infectious disease. However, it is clear that the MMP/TIMP system changes the ECM composition and biophysics and its presentation of bioactive molecules, generating environmental cues that are detected and processed by immune cells into signalling events that direct their behaviour and response to infection. ECM post‐translational modification Post‐translational modifications (PTMs) add complexity to the ECM. Some are generated by proteolytic cleavage, while others are generated by citrullination of arginine, glycosylation, cross‐linking, hydroxylation of prolines, nitrosylation of tyrosines and aspartate isomerization (reviewed in ref. 7). Given the ability of pathogens to hijack host enzymes or secrete enzymes targeting host molecules, it is tempting to ask whether PTMs in the ECM are altered in infection. Indeed, the Porphyromonas gingivalis enzyme peptidylarginine deiminase can convert arginine residues to citrulline in mammalian ECM proteins, including fibrinogen, collagen II, fibronectin and tenascin‐C.72-76 Although arginine is positively charged at neutral pH, citrulline is uncharged, increasing protein hydrophobicity and, hence, altering protein three‐dimensional structure and function. Notably, Porphyromonas gingivalis periodontal infection has been linked to rheumatoid arthritis, an autoimmune disease of the joints characterized by high levels of citrullinated proteins and anti‐citrullinated ECM protein antibodies.77 Trypanosoma cruzi, the aetiological agent of Chagas disease, which features extensive inflammation and fibrosis of the heart, has been reported to increase the expression of lysyl oxidase (LOX).78 This enzyme carries out cross‐linking of collagen fibres thereby altering matrix stiffness, which has been linked to cancer metastasis.79 By irreversibly altering collagen structure and function, LOX has been proposed to cause dysfunction of cardiomyocytes and, in turn, of the heart in Chagas disease. Similarly, dengue virus infection has been shown to suppress the expression of cartilage‐associated protein (CRTAP), alongside the protein associated to tight junctions (PATJ). CRTAP associates with the proteoglycan leprecan, which has collagen prolyl 3‐hydroxylase activity, and cyclophilin B in the endoplasmic reticulum. This trimeric complex is required for proline 3‐hydroxylation of collagen and, hence, collagen assembly. As the levels of CRTAP mRNA negatively correlate with viral replication, the authors of the study have speculated that CRTAP, together with PATJ, restrict dengue infection by influencing cell–cell adhesion.80 While evidence supporting a link between specific PTMs of ECM proteins and diseases such as arthritis and cancer is accumulating, the implications of altered PTMs of ECM components during infection are only beginning to emerge. For example, collagen fibre cross‐linking mediated by LOX can significantly alter tissue structure and ECM mechanics. Mammoto et al. recently showed that LOX‐dependent changes in ECM mechanics control vascular permeability and pulmonary oedema. In vivo, mouse lungs treated with LPS, which contributes to pulmonary oedema and acute respiratory distress syndrome in patients with sepsis,81 become much stiffer than untreated lungs and exhibit enhanced vascular permeability. Increased LOX expression and LOX and LOX1 protein isoform activity control alveolar architecture and vascular permeability, which are restored by LOX activity inhibition.82 Macrophages: not just destroyers of the ECM In bacterial and viral infection, activated macrophages [e.g. M(IFN‐γ), M(LPS)] have long been implicated in ECM destabilization and destruction through the secretion of tissue‐degrading enzymes, including MMP‐9. Similarly, parasitic infections involve activated macrophages [i.e. M(IL‐4)], which release proteases such as MMP‐1 and MMP‐12.83 However, macrophages can also produce a number of ECM proteins. Increasing evidence of this and its implications are discussed below. Fibronectin is the first ECM glycoprotein reported to be produced by human macrophages and IFN‐γ‐stimulated mouse peritoneal macrophages.84, 85 Moreover, bacterial components induce tenascin‐C expression in human monocyte‐derived and mouse bone‐marrow‐derived macrophages.53, 86 Lipopolysaccharide from Porphyromonas gingivalis induces thrombospondin‐1 production in THP‐1 cells,87 while LPS from Escherichia coli and IFN‐γ up‐regulate galectin‐1 and galectin‐3, including five galectin‐3 truncated forms, in primary human macrophages.88 In mice with viral myocarditis, macrophages infiltrating the heart are the main producers of osteopontin.48 Notably, in murine macrophages, LPS causes the formation of chromosomal loops in the osteopontin promoter by bridging nuclear factor‐κB (NF‐κB) and activator protein‐1 together, leading to osteopontin transcription,89 which is negatively regulated by GSK3b.90 Macrophage expression of proteoglycans has also been demonstrated. Treatment of bone marrow‐derived and alveolar macrophages with Escherichia coli LPS results in rapid induction of versican and hyaluronan synthase 1, and simultaneous inhibition of the major hyaluronan‐degrading enzymes (hyaluronidases 1/2).91 Serglycin, decorin and biglycan are also secreted by LPS‐activated mouse peritoneal macrophages.92-94 By using inhibition, chromatin immunoprecipitation and NF‐κB reporter gene assays, some of these studies have demonstrated that pathogenic activation of the NF‐κB signalling pathway downstream of TLR4 leads to ECM molecule transcription.86, 89, 93-95 Importantly, in the case of tenascin‐C, biglycan and decorin, which can activate TLR4, this can promote autocrine loops of inflammation.86, 93, 94 Hence, the infected cellular microenvironment influences TLR function and, in turn, TLR activation affects the microenvironment. Intriguingly, there is mounting evidence that macrophages can synthesize collagen molecules. In Drosophila, phagocytes (haemocytes) produce functional collagen IV, which controls key signalling events in the germline stem cell niche.96 The first reports of collagen synthesis by mammalian macrophages were published in the 1990s. The first showed collagen I synthesis in mouse peritoneal macrophages and the second demonstrated collagen VIII synthesis and secretion in human macrophages, which was decreased by IFN‐γ and LPS treatment.97, 98 Collagen VIII is a short‐chain, non‐fibrillar collagen that forms unique hexagonal lattice structures and possesses both structural and signalling properties. Later, human macrophages were shown to secrete collagen VI, which forms beaded filaments with a multidomain structure that interact with ECMs and cell surface receptors to anchor interstitial structures and cells within tissues. Expression of collagen VI was decreased by IFN‐γ and LPS, but increased upon IL‐4 treatment.99 Recently, the expression of all 28 collagen‐encoding mRNAs was quantified in steady‐state and LPS‐activated primary human macrophages and compared with that of human dermal fibroblasts, an abundant matrix source.95 Steady‐state macrophages expressed basal levels (lower than those in dermal fibroblasts) of collagen mRNAs with the exception of collagen III, X, XI, XVI, XX and XXVI. However, LPS specifically increased the expression of fibril‐associated collagens with interrupted triple helices (FACITs; collagen VII, XII, XV, XIX and XXI), the collagenase‐resistant collagen V, the collagen‐containing von Willebrand factor collagen XXVIII and collagen I, IV, XVIII, XXV and XXVII. Collagen II, VIII, IX, XIII, XIV, XXIII and XXIV expression was not increased. LPS also down‐regulated the expression of collagen VI, confirming previous studies,99 and collagen XIII and XVII.95 By secreting collagens, depending upon their mode of activation, macrophages may contribute to the ECM, and therefore to tissue stabilization and repair, and to cell–cell and cell–matrix interactions (e.g. in vitro, monocytes adhere strongly to collagen VI99). Furthermore, macrophages may bind to their secreted collagen molecules as they express several receptors known to interact with collagen (e.g. integrins and proteoglycans). However, collagen secretion by macrophages and its potential role in macrophage adhesion and the immune response in vivo remain to be clarified. The ECM: an integral part of the innate immune response to infection? Antimicrobial activity of the ECM The innate immune system employs endogenous peptides like α‐defensin and LL‐37, which bind to heparin and dermatan sulphate glycosaminoglycans and have antimicrobial properties. During the inflammatory response to infection, tissue‐degrading enzymes generate bioactive ECM fragments. A number of studies showed that heparin‐binding peptides derived from laminin isoforms, vitronectin, thrombospondin and fibronectin, exert antimicrobial activities against Gram‐positive and Gram‐negative bacteria, and the fungus Candida albicans.100-102 Certain ECM proteins are also found in biological fluids. One such protein is tenascin‐C, which has been found in human breast milk (2·2–671 μg/ml) where it acts as an innate broad‐spectrum human immunodeficiency virus 1 (HIV‐1) ‐neutralizing protein.103 Tenascin‐C directly captures HIV‐1 virions by binding to the HIV‐1 envelope gp120 protein at a CD4‐inducible epitope that overlaps the chemokine co‐receptor binding site. Accordingly, tenascin‐C depletion abolishes the HIV‐1‐neutralizing activity of milk.103 Direct antimicrobial activity has also been reported for the ECM‐associated protein MMP‐12, which is abundantly expressed in mature tissue macrophages and mobilized to macrophage phagolysosomes after the ingestion of bacteria. Inside phagolysosomes, MMP‐12 adheres to bacterial cell walls and disrupts cellular membranes, killing the bacteria. Notably, the C‐terminal domain of MMP‐12, but not its catalytic domain, contains a four‐amino‐acid sequence on an exposed β loop of the protein that is unique in nature and confers antimicrobial activity.104 Together, these data may help the search for safe, endogenous antimicrobial molecules from complex biological mixtures. Furthermore, binding epitopes could serve as templates for de novo synthesis of novel antimicrobial molecules. ECM‐mediated recognition of microbial pathogens, macrophage activation and phagocytosis The innate immune system employs highly conserved receptors, namely PRRs, to recognize conserved motifs in microbial pathogens, called pathogen‐associated molecular patterns. Mindin, a member of the mindin‐F‐spondin family of secreted ECM proteins, has emerged as a unique pattern recognition molecule in the ECM for microbial pathogens and has been proposed to function as an integral part of the innate immune response.105 He et al., showed that genetic ablation of mindin confers resistance to LPS‐induced shock and systemic Salmonella typhimurium and Streptococcus pneumoniae infections in vivo. Moreover, mindin‐null mice feature impaired bacterial clearance in lungs infected with Gram‐positive group B streptococcus or Haemophilus influenzae. In vitro, macrophages and mast cells lacking mindin display impaired TNF‐α and IL‐6 production and defective phagocytosis. By using recombinant mindin, the authors showed that this ECM protein recognizes carbohydrate moieties of Gram‐positive and Gram‐negative bacterial components and, by binding to them, it agglutinates bacteria. As glucose inhibited not only mindin binding to pathogens but also macrophage activation by LPS, the authors concluded that mindin‐mediated carbohydrate recognition of microbial pathogens is a secondary stimulation necessary for the activation of macrophages and mast cells105 (Fig. 1). Notably, mindin is not a universal, but is a specific pattern recognition molecule as it only recognizes and opsonizes certain bacteria. Following this, the innate immune function of mindin has been extended to include promoting influenza virus clearance from the nasal cavity by allowing efficient macrophage activation.106 Furthermore, the proteoglycan lumican, whose core protein contains tandem repeats of leucine‐rich motifs similarly to PRRs, interacts with CD14 on the surface of macrophages and neutrophils, promoting CD14‐TLR4‐mediated responses to LPS (Fig. 1). Hence, lumican‐null mice are hyporesponsive to LPS‐induced septic shock.107 In a Pseudomonas aeruginosa model of lung infection, mortality of lumican‐deficient mice is increased as animals fail to clear bacteria from tissues. This study showed that CD14‐mediated phagocytosis of Escherichia coli and Pseudomonas aeruginosa bacteria by macrophages is impaired in the absence of lumican and identified Tyr‐20 as a vital residue for CD14 binding and phagocytosis.108 Finally, infection of the cornea with Pseudomonas aeruginosa readily increases lumican expression before inflammatory cell infiltration, and lumican‐null mice display poor resolution of bacterial keratitis and sustained production of pro‐inflammatory cytokines.109 Another ECM protein that senses a number of microbial pathogens is galectin‐3, which binds to carbohydrate structures on glycoproteins and glycolipids (e.g. N‐acetyl‐d‐lactosamine and LPS) from (myco)bacteria, protozoan parasites and yeast.110 Although the in vivo function of galectin‐3 during infection has not been fully investigated, upon microorganism recognition, it contributes to macrophage‐mediated phagocytosis, at least in vitro111 (Fig. 1). Whether these ECM components exert the same essential immune functions in humans represents an outstanding, important question. Leucocyte population balance in infection: emerging roles for ECM components Severe infection demands large numbers of leucocytes that are compensated by the emergency myelopoiesis response, which is initiated by activated PRRs and cytokines, including IL‐6, granulocyte–macrophage colony‐stimulating factor and granulocyte colony‐stimulating factor. This protects the host from systemic infection by quickly generating the required leucocyte population. Kanayama et al.112 have recently found that osteopontin skewed the balance of myeloid and lymphoid cell populations during systemic infection with Candida albicans. Specifically, the authors showed that osteopontin limited the supply of neutrophils and Ly6C+ monocytes–macrophages by enhancing the apoptosis of common myeloid and granulocyte–macrophage progenitors through a down‐regulation of the expression of the apoptosis inhibitor survivin. This resulted in greater fungal load in kidneys and significantly higher mortality of wild‐type mice with systemic fungal infection compared with osteopontin‐deficient littermates. The detrimental effect of osteopontin was observed early, 24 hr after infection.112 However, it is unclear if this effect is maintained, exacerbated or reversed at later stages of infection. Dendritic cells (DCs) are the main antigen‐presenting cells and, upon capturing microbial pathogens, mature and migrate to lymphoid tissues where they activate naive T cells. Distinct classes of microbes elicit lineage‐specific responses from the effector T‐cell repertoire. Type 1 helper T (Th1) cells are involved in infection by intracellular bacteria and viruses, Th2 cells in parasitic infection, and Th17 cells in infection by extracellular pathogens and facultative and obligate intracellular bacteria and fungi. Regulatory T cells hold the inflammatory response in check. Specific ECM proteins have been shown to contribute to the T‐cell polarizing function of DCs without affecting DC development. For instance, generation of Th17 cells by Escherichia coli LPS or Mycobacterium tuberculosis stimulated bone marrow‐derived DCs from tenascin‐C‐null mice is significantly impaired.113 Furthermore, the expression of galectin‐3 in DCs controls the magnitude of T‐cell priming in vitro and in vivo during helminthic infection with Schistosoma mansoni. Galectin‐3‐deficient mice have significantly fewer T cells in their spleen and higher cellular and humoral Th1 responses.114 Although this study shows that galectin‐3 expression by DCs modulates the proliferation and cytokine release by T cells, it does not explain the mechanism responsible for the biased Th1 response. Efficient T‐cell priming by DCs has also been shown to depend on mindin.115 When DCs from mindin‐null mice are activated with bacterial components, including LPS from Salmonella typhosa or Escherichia coli and lipoteichoic acid from Staphylococcus aureus, CD4+ T‐cell priming is 60–70% lower than that of wild‐type mice. Investigation of this demonstrated that DCs interact with mindin via integrins α4β1 and α5β1, leading to up‐regulated expression of the Rho GTPases Rac1/2, which are known to regulate DC priming of T cells.115 As DCs link innate to adaptive immunity and unbalanced effector T‐cell populations lead to pathological inflammation, understanding how the ECM can regulate T‐cell responses is crucial. Transcriptional and post‐transcriptional roles for ECM molecules in host defence signalling pathways Pathogen recognition via PRRs initiates inflammatory signalling pathways that are tightly regulated to allow microbial clearance with minimal damage to the host. Recent research implicates a role for ECM and ECM‐associated proteins in regulating inflammatory networks at the transcriptional and post‐transcriptional levels during the immune response to infection. An elegant study by Marchant et al.69 found a transcriptional role for MMP‐12 (macrophage elastase) in immunity against viral infection. During coxsackievirus type B3 and respiratory syncytial virus infections, MMP‐12‐null mice display increased viral load, mortality and lower levels of IFN‐α, which is essential for viral immunity. Mechanistically, secreted MMP‐12 is taken up by virus‐infected cells and traffics to the nucleus, where it binds to the NFKBIA promoter, driving its transcription, which is essential for optimal IFN‐α secretion and host protection. Additionally, MMP‐12 regulates specific substrates by two distinct mechanisms: (i) through DNA binding of gene exons (e.g. exons encoding PSME3, the immunoproteasome cap protein, and SPARC‐like protein 1, which decreases their mRNA and protein levels in MMP‐12‐null mice); and (ii) extracellularly, through substrate protein cleavage (e.g. IFN‐α receptor 2 binding site). Hence, MMP‐12 clears systemic IFN‐α and, accordingly, selective inhibition of extracellular MMP‐12 in infected wild‐type mice elevates systemic IFN‐α levels and reduces viral replication.69 At the post‐transcriptional level, a role for decorin and tenascin‐C has been found in regulating microRNAs in LPS‐induced sepsis.53, 93, 116 Merline et al. detected increased decorin levels in patients with sepsis and mice with LPS‐induced sepsis, and elevated IL‐10 amounts in decorin‐null mice. They demonstrated that, in the presence of LPS, decorin reduces the levels of the anti‐inflammatory cytokine IL‐10 through two mechanisms. First, it activates extracellular signal‐regulated kinase and p38 mitogen‐activated protein kinases downstream of TLR2 and TLR4, thereby inducing the expression of the pro‐inflammatory modulator programmed cell death 4 (PDCD4), which translationally represses IL‐10. Second, decorin inhibits TGF‐β1 signalling, leading to lower levels of the microRNA miR‐21, which represses PDCD4 expression and so decreases IL‐10 levels.93 Soon after, tenascin‐C was shown to orchestrate the secretion of specific cytokine subsets in response to LPS. Specifically, tenascin‐C regulates the biosynthesis of the LPS‐responsive miRNA miR‐155, allowing optimal TNF‐α production in macrophages and effective immune response to LPS in vivo.53 Hence, specific ECM and ECM‐associated proteins possess previously unknown transcriptional and post‐transcriptional regulatory activities, which fine‐tune the innate immune response to infection. The ECM in infectious granulomas Tuberculosis, syphilis, toxoplasmosis, infectious mononucleosis and measles are a few examples of infectious diseases characterized by the formation of granulomas. Traditionally considered host‐protective structures, infectious granulomas are compact, organized immune cell clusters that are generated in response to specific pathogens. Granulomas contain large numbers of mature macrophages, which can fuse into multinucleated giant cells or differentiate into foam cells. Neutrophils, dendritic cells, B, T and natural killer cells, and fibroblasts are also found in granulomas, which are surrounded by epithelial cells. Granulomas also contain ECM proteins, whose expression and function in infectious granulomatous disease pathogenesis has only recently been investigated. In humans, osteopontin has been detected in granulomas of diverse aetiology;117 in those caused by Paracoccidioides brasiliensis, it localizes in ECM, macrophages and multinucleated giant cells at the centre of lesions in the early phase of infection.118 In tuberculosis granulomas, osteopontin is markedly expressed within lymphocytes, macrophages, epithelioid cells and multinucleated giant cells, but not in the central necrotic core.54 These granulomas also stain strongly for tenascin‐C in the surrounding fibrotic rings and weakly inside, in the ECM. A diffuse ECM‐associated staining of galectin‐9 is detected in the granuloma and in epithelioid and multinucleated giant cells. Notably, osteopontin, tenascin‐C and galectin‐9 are absent in non‐infectious Crohn disease granulomas.54 Analysis of human lung biopsies from patients with atypical mycobacteriosis and tuberculosis revealed expression of tenascin‐C and precursor proteins of collagens I and III around granulomas. Precursor proteins of collagen I were also found within granulomas that co‐localized with myofibroblasts.119 In mice infected with Paracoccidioides brasiliensis, Gonzalez et al. detected increased expression of laminin, fibronectin, fibrinogen, collagen I, collagen III, elastic fibres and proteoglycans during granuloma formation.120 Analysis of their arrangement showed that they were mostly surrounding the granuloma, but sporadically inside it. Initially arranged in a disorganized manner, ECM fibres later acquired a compact, concentric arrangement, which originated from an anchorage point that may contribute to tissue integrity and enhance distribution of growth factors and cytokines.120 Notably, during chronic mycobacterial infection, the fibrinolytic system has been shown to limit progressive fibrosis with plasminogen regulating the turnover of ECM proteins within the granuloma.121 Recent studies on ECM turnover in tuberculosis granuloma have helped to rewrite tuberculosis immunopathology. Traditionally considered a host‐protective structure that ‘quarantines’ the infecting mycobacteria, tuberculosis granuloma has been implicated in the expansion and dissemination of infection. Specifically, caseous necrosis leading to ECM destruction and bacterial dissemination was thought to be the cornerstone of tuberculosis pathogenesis. Conversely, collagen destruction has now been proposed to initiate caseous necrosis. Elkington et al.122 have first shown that MMP‐1‐expressing mice develop collagen destruction within granulomas upon infection with Mycobacterium tuberculosis in the absence of caseous necrosis. They then demonstrated that proteolytic collagen destruction of the lung ECM is the initial pathological event that reduces the survival of Mycobacterium tuberculosis‐infected cells, resulting in caseous necrosis and cavitation, and so diverting the immune response in favour of the pathogen. Conversely, intact collagen fibrils increase survival of infected cells.123, 124 In line with this, Parasa et al. reported up‐regulation of MMP‐1, MMP‐3, MMP‐9 and MMP‐12 in a human lung‐tissue model and in biopsies from patients with non‐cavitary tuberculosis. Global MMP inhibition via marimastat reduced granuloma formation and bacterial load.125 Future work should take into account the hypoxic conditions in infectious granulomas and include unbiased global analyses of ECM and ECM‐associated molecules in granulomas at various disease stages and gain‐ and loss‐of‐function experiments in three‐dimensional systems and/or genetically modified animals to understand the role of the ECM in granuloma formation and function. Concluding remarks and future perspectives The ECM and the innate immune response to infection are inextricably linked. Largely ignored or overlooked, the diverse yet specific functions of the ECM in infection influence the establishment and dissemination of microbial pathogens in host tissues as well as the outcome of the immune response to the infection (Fig. 2). In addition to the studies discussed here, ECM immunological research, which is expanding into the areas of prion disease,126 virus transmission,127 exosomes in viral pathogenesis128 and vaccine development,129 shows the breadth and complexity of ECM activity and regulation in infection. The ECM undergoes significant changes upon microbial invasion, magnifying the complexity of the cellular microenvironment at sites of infection. This presents challenges in setting up appropriate model systems and identifying the ECM and immunological pathways that are directly responsible for the outcome of individual infectious diseases. Unbiased omics, systems biology and genome editing approaches are promising resources for defining these pathways, designing mechanistic studies, and, in the longer‐term, elucidating them in the context of the microbiota. As antimicrobial resistance is of global concern and tackling it is becoming increasingly challenging, investigating the now evident role of the ECM in infection may reveal novel therapeutic strategies or improve existing ones. It may also inform biomaterials and tissue engineering in their effort to prolong the lifespan and integrity of medical devices that are compromised by infection. Acknowledgements The authors are supported by an Anne McLaren Fellowship (University of Nottingham; awarded to AMP) and a BBSRC‐DTP studentship (HT). We thank E.P. Ling for assistance with the literature search and N. Zordan for help with the figures. Disclosures None to declare. References Notes : GI, gastrointestinal; UTI, urinary tract infection; LpfAI, long polar fimbrae subunit 1; SfbII, fibronectin surface binding protein II; Fba, fibronectin binding protein; MntC, manganese transport protein C; MisL, autotransport protein MisL; FimB, type I fimbriae regulatory protein FimB; gtf, glucosyltransferase; pilB, type 4 fimbrial assembly protein; EcbA, E. faecium collagen binding protein A; MIP, macrophage infectivity potentiator; YadA, adhesin YadA; TcCRT, Trypanosoma cruzi calreticulin; DdpA/ DdpB, decorin binding protein A and B; SgrA, serine‐glutamate repeat containing protein A; ClfA/ClfB, clumping factor A and B. Cwp84, putative cell surface‐associated cysteine protease; HRgpA and RgpB, arginine‐gingipains; Kgp, lysine‐gingipains; UTI, urinary tract infection. Citing Literature Number of times cited: 1 Abha Sahni, Hema Narra, Jignesh Patel and Sanjeev Sahni, MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1, Cells, 10.3390/cells7120240, 7, 12, (240), (2018). Crossref
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We have previously reported that a group of host cellular microRNAs (miRNAs; miR-34a-5p, miR-122-5p, miR-145-5p, miR-146a-5p, miR-210-3p) are released into the blood during sepsis, some of which are capable of inducing complement activation, cytokine production, and leukocyte migration.
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Gilbert C FAURE
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Review Free access | 10.1172/JCI90962 The role of the complement system in cancer Vahid Afshar-Kharghan First published March 1, 2017 - More info Abstract In addition to being a component of innate immunity and an ancient defense mechanism against invading pathogens, complement activation also participates in the adaptive immune response, inflammation, hemostasis, embryogenesis, and organ repair and development. Activation of the complement system via classical, lectin, or alternative pathways generates anaphylatoxins (C3a and C5a) and membrane attack complex (C5b-9) and opsonizes targeted cells. Complement activation end products and their receptors mediate cell-cell interactions that regulate several biological functions in the extravascular tissue. Signaling of anaphylatoxin receptors or assembly of membrane attack complex promotes cell dedifferentiation, proliferation, and migration in addition to reducing apoptosis. As a result, complement activation in the tumor microenvironment enhances tumor growth and increases metastasis. In this Review, I discuss immune and nonimmune functions of complement proteins and the tumor-promoting effect of complement activation. Introduction The complement system is a cascade of serine proteases encoded by genes originating from the same ancestral genes as coagulation proteins (1). Like the coagulation system, complement activation involves several steps, is tightly regulated, and requires both plasma and membrane proteins (2, 3). Many complement proteins possess dual functions that provide crosstalk between the complement system and other effector and regulatory systems. As a result, the complement system participates in adaptive immunity, hemostasis, neuroprotection and synaptic pruning, and organ development in addition to its role in innate immunity. It is also involved in a diverse array of pathologic conditions, such as thrombotic disorders, autoimmune disorders, schizophrenia, alloimmune responses including allograft rejection and graft-versus-host disease, and cancer. The complement system’s role in fighting invasive pathogens has been extensively studied (4, 5), but recent discoveries provide new perspectives on the complement system’s function in the extravascular and interstitial tissue compartment. These discoveries illustrate an important role for complement proteins in cell-cell and stroma-cell communications. In this Review, I briefly discuss activation, regulation, immune, and nonimmune functions of the complement system to provide a framework for examining the role of complement in cancer. Activation of the complement system The complement system is activated by three major pathways: the classical pathway, via antigen-antibody complexes; the alternative pathway, via any permissive surfaces; and the lectin pathway, via binding of pattern-recognizing mannose-binding lectins (MBLs) to carbohydrate ligands on the surface of pathogens (Figure 1 and refs. 6–9). The convergence point for all complement activation pathways is the formation of the C3 convertase complex on the surface of targeted cells, summarized in Figure 1, A–C. After forming C3 convertase, complement is able to carry out its effector functions. Figure 1 Complement activation. (A) The classical pathway is initiated by a complement-fixing antibody binding to an antigen on targeted cells. C1q binds to the antibody’s Fc domain in the antibody-antigen complex. C1r and C1s assemble on C1q, C1r cleaves and activates C1s, and activated C1s cleaves C4 and C2 into C4b and C2a, respectively. C4b and C2a form the C3 convertase C4bC2a. (B) In the lectin pathway, MBL binds to repetitive sugar moieties such as mannose. MBL and MASP2 then form a C1-like complex. Activated MASP2 in MBL-MASP2 complex cleaves C4 and C2 and generates C3 convertase (C4bC2a). (C) In the alternative pathway, small amounts of hydrolyzed plasma C3 [C3(H2O)] bind to factor B, which forms the C3(H2O)Bb complex with help from factor D. C3(H2O)Bb cleaves additional plasma C3 to generate highly active C3b, which binds to cell the surface. On a complement-activating surface, C3b binds Bb (produced by factor D–mediated cleavage of factor B) and generates C3bBb (the alternative pathway’s C3 convertase). (D) Regardless of the initiation steps, C3 convertase deposits additional C3b molecules and generates C3a. If it remains intact, C3 convertase binds to additional C3b to generate C5 convertase. C5 convertase cleaves C5 to generate C5b. (E) C5b binds to C6, C7, and C8, forming a C5b-8 complex, which polymerizes several C9 molecules, forming the cytolytic MAC. In all three complement activation pathways, C3 convertase complex cleaves C3 molecules to C3a, one of the two major anaphylatoxins, and to C3b, a potent opsonin. Binding of C3b molecules to the surface of cells or cell debris in a process called opsonization marks them for phagocytosis by macrophages. Surface-bound C3b and its degradation products are ligands for complement receptors CR1, CR3, and CR2 that are expressed on myelomonocytic cells, lymphocytes, and follicular dendritic cells. Binding of C3b and its degradation products to correspondent receptors are crucial to cell-cell interactions in the innate and adaptive immune responses and in the removal of complement-coated apoptotic and necrotic cells. Propagation of complement activation by C3 convertase results in the generation of the C5 convertase complex on the cell surface. C5 convertase then cleaves C5 to C5a and C5b. C5a is a potent anaphylatoxin and recruits neutrophils to areas of inflammation and tissue damage. C5b forms a complex with C6 and C7 that may insert into cell membrane, and subsequently be joined by C8 and multiple C9 to form the membrane attack complex (MAC or C5b-9 complex; Figure 1D). Deposition of an adequate number of MACs disrupts the phospholipid bilayer of the cell membrane, leading to massive calcium influx, loss of mitochondrial membrane potential, and cell lysis. However, MAC deposition at sublytic concentrations on cell membrane has a different result, activating intracellular signal transduction and cell proliferation (10). Eukaryotic cells have developed several defense mechanisms to counteract the dire consequences of MAC accumulation at the cell surface, including expression of complement regulatory proteins (CRPs) that disassemble MAC (i.e., CD59, vitronectin, and clusterin), and endocytosis or shedding of MAC from the cell surface. Thus, the three main consequences of complement activation are tagging of cells by C3b degradation products for phagocytosis; chemotaxis of inflammatory cells in response to C3a and C5a; and MAC-mediated cell lysis. As described below, complement activation end products affect tumor growth by altering cancer cell behavior and modulating the immune response to the tumor. Regulation of the complement system The complement system’s ability to cause cellular damage is strictly controlled at several steps, both in the fluid phase and on the cell surface (6). In the classical and lectin pathways, C1 inhibitor (C1INH) binds to and inactivates C1r, C1s, and MBL-associated serine proteases (MASPs). The activities of other CRPs can be categorized into two major groups: (a) decay-accelerating activity, which breaks up the C3 convertase complex, as can be seen in C4-binding protein (C4bp), CR1, decay-accelerating factor (DAF, also known as CD55), and factor H; and (b) membrane cofactor activity, which acts as a cofactor for the factor I–mediated cleavage of C3b or C4b to their inactive degradation products, iC3b and iC4b, respectively. CRPs with membrane cofactor activity include C4bp, CR1, membrane cofactor protein (MCP, or CD46), and factor H. Another important CRP is CD59, which is expressed on many different cell types and prevents assembly of MAC on the cell membrane. The anaphylatoxins C3a and C5a are complement activation products that are rapidly inactivated in plasma by carboxypeptidases, particularly carboxypeptidase N (11). CRPs are overexpressed by many cancer cells and may be used as potential therapeutic targets. Immune function of the complement system The complement system is an ancient defense mechanism preceding adaptive immunity (12). It can be activated by pattern-recognition molecules and natural antibodies (13). Complement system activation and generation of anaphylatoxins orchestrate an inflammatory response to pathogens (12, 14). Anaphylatoxins activate macrophages, neutrophils, mast cells, basophils, and eosinophils, resulting in their degranulation and the production of cytokines, which in turn causes vasodilation, increases vascular permeability, and enhances neutrophil extravasation and chemotaxis (13). The complement system links innate immunity to adaptive immunity. Complement deficiency impairs both B and T cell responses (15). The effect of complement on the B cell response is mediated by CR2 on B cells and follicular dendritic cells. Activation of the classical pathway on the surface of an antigen tags that antigen with C3d, enabling its binding to CR2 on B cells. CR2, CD19, and CD81 form a B cell coreceptor complex, and CR2 engagement with C3d enhances signaling through antigen-encountered B cell receptors and decreases the activation threshold of B cells (12, 15). The interaction between CR2 on follicular dendritic cells and C3d on antigens is important for antigen presentation to naive and primed B cells in the germinal center of lymph nodes, in the maturation of B cells, and in the generation of memory B cells. The role of complement proteins in the cognate interaction between antigen-presenting cells (APCs) and T cells is important in the T cell immune response (16). In addition to systemic production in the liver, complement proteins are also produced locally by T cells and APCs (17–20). The effects of complement proteins on activation, proliferation, and differentiation of T cells are mediated by the local complement activation, by production of C3a and C5a at the interface of T cells and APCs, and through anaphylatoxin receptors on T cells and APCs (17–19, 21, 22). Reducing the number of C3a and C5a receptors (C3aR and C5aR, respectively) on T cells or APCs impairs T cell immunity. Complement proteins and receptors are involved in different stages of the interaction between APCs and T cells. APCs produce C3 and express C3aR and C5aR, both of which are essential for their maturation and differentiation (19) and for effective antigen presentation to T cells (17, 23, 24). C3- or C3aR-deficient APCs are much less potent in inducing a T cell immune response compared with WT APCs (19, 25). After APCs present antigen to T cells, C5aR on the T cells is required for their proliferation. Binding of C5a to C5aR on T cells has both antiapoptotic and pro-proliferative effects (22). Nonimmune function of the complement system Cell-cell and stroma-cell interactions mediated by complement proteins regulate several physiologic processes, such as collective cell migration during embryogenesis (26), synaptic pruning during brain development (27–30), cell proliferation and differentiation during liver regeneration (31) and bone development (32, 33), and hematopoietic stem cell migration and engraftment during hematopoiesis (34). Complement and cancer The surge of interest in cancer immunotherapy is mainly focused on manipulating function or number of cytotoxic T cells. However, two important reasons justify studying the role of complement activation in cancer progression and the effect of complement manipulation in cancer therapy. First, the complement system is an important component of the inflammatory response, and inflammation is involved in various stages of tumorigenesis and cancer progression (35). Second, complement activation regulates adaptive immune response (15) and might have a role in regulating T cell response to tumors. Complement system in inflammation and tumorigenesis. Tumor-promoting inflammation has an important role in carcinogenesis and cancer progression (36–38). A series of elegant experiments established that activation of the complement system is an important component of tumor-promoting inflammation. Bonavita et al. showed that C3-deficient mice were protected against chemical carcinogenesis in mesenchymal and epithelial tissues (39), mainly because of reduced inflammation. Authors identified a humoral component of innate immunity, the long pentraxin PTX3, as an important negative regulator of inflammation and complement activation. PTX3-deficient mice were susceptible to chemical carcinogenesis, displaying an increased number of tumor-associated macrophages with M2 phenotype and increased concentration of CCL2 chemokine inside tumors. The tumor-promoting inflammation induced by PTX3 deficiency was complement-dependent and completely reversed after removal of C3, as manifested by a reduction in the susceptibility of Ptx3–/– C3–/– mice to chemical carcinogenesis. Similarly, treatment with the C5aR antagonist PMX-53 reversed the susceptible phenotype of Ptx3–/– mice without affecting the rate of tumorigenesis in Ptx3+/+ mice. Activation and regulation of complement pathways in tumors. Expression of complement and CRPs is increased in malignant tumors and cancer cell lines (summarized in Table 1). Complement proteins, C3 degradation products, and complement activation products (i.e., C5a, C3a, and C5b-9) are easily detectable in various types of cancer, consistent with complement activation inside these tumors. Table 1 Complement proteins in cancer The main pathway involved in activation of complement inside tumors is unclear, and evidence supports activation of each complement pathway in malignant tumors (40). To make matters more complicated, cancer cell membrane-bound serine proteases can also cleave C5 and generate C5a without complement activation (41). Additionally, complement proteins expressed in tumors might also play a role in cancer progression independent of complement activation, as was shown for C1q in a syngeneic murine model of melanoma, where C1q expression affected angiogenesis, tumor progression, and metastasis (42). In this murine model, C1q was expressed in endothelial cells, spindle-shaped fibroblasts, and tumor-infiltrating myeloid cells independently of C4. Lack of C4 coexpression in C1q-expressing tumors hints at a role for C1q in tumor progression independent of the classical pathway. Expression of CRPs, including both membrane proteins (CD55, CD59, MCP, or CD46) and soluble proteins (factor H and factor H–like proteins), is increased in cancer cells (43), although the overexpression of CRPs is heterogeneous among different cancer types and even between different tumor specimens of the same type of cancer (44). One interpretation of the presence of both complement activation products and CRPs in tumors is that complement activation is a host defense mechanism against cancer, and cancer cells resist complement attack by overexpressing CRPs. However, as discussed later in this Review, several recent studies do not support this interpretation and suggest another scenario in which local complement activation inside tumors enhances tumor growth. Complement activation: antitumor or protumor? Evidence for the effects of complement on malignant transformation of epithelial cells and progression of cancer has evolved based on several recent studies showing complex and sometimes contradictory findings. This complexity is similar to the complex role of inflammation in cancer (45). Although inflammatory cells and cytokines are important in immune surveillance, exemplified by the benefit of bacillus Calmette-Guérin therapy in early stages of bladder cancer, chronic inflammation promotes carcinogenesis and tumor growth. Even immune cells, such as macrophages, can have both pro- and antitumor phenotypes. Despite this multifaceted picture, most evidence points toward a protumor effect of chronic inflammation (45). The long-held view of complement activation as an antitumor defense mechanism is based on two main concepts: first, the complement system’s participation in immune surveillance against malignant cells, and second, complement-dependent cytotoxicity of therapeutic monoclonal antibodies. I will discuss these concepts below, and summarize new information pointing toward a protumor effect of complement activation inside tumors. Complement and immune surveillance. The complement system’s ability to distinguish self from non-self makes it an important part of the innate immune response to invading pathogens (46). Expression of non-self antigens and lack of CRPs on microbes make them optimal targets for complement detection and, later on, complement-mediated elimination. Similarly, expression of danger signals and neoantigens by apoptotic cells and cellular debris optimizes their detection and removal by the complement system. Cancer cells, on the other hand, mostly express the same proteins as their normal epithelial cell counterparts, albeit occasionally with a different density. Furthermore, overexpression of CRPs by cancer cells limits immune surveillance by the complement system (3, 43, 46, 47). Putting these findings together, one can conclude that cell-mediated immunity plays a more important role than humoral immunity in immune surveillance against cancer cells (48, 49), and effectiveness of complement in early detection and elimination of cancer cells is uncertain (50). Complement-dependent cytotoxicity. Complement activation was considered detrimental to cancer cells via complement-dependent cytotoxicity, which causes cancer cell lysis via MAC accumulation or phagocytosis of opsonized cancer cells by macrophages and neutrophils. Complement-dependent cytotoxicity is considered to be the main mechanism for the effectiveness of antitumor monoclonal antibodies. Rituximab, an anti-CD20 antibody against malignant B cells, is among the oldest and most widely used therapeutic monoclonal antibodies. Although in vitro and in vivo studies show that rituximab activates the classical complement pathway (51, 52), the notion that its therapeutic benefits are mainly mediated by induction of complement attack on malignant B cells is questionable. In fact, the antitumor effect of rituximab was inhibited by deposited complement proteins on B cells (53), and was enhanced in complement-deficient mice (54). Therefore, the extent to which complement-dependent cytotoxicity contributes to other immunologic effects of rituximab, i.e., antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis, is unknown. Other studies on the therapeutic mechanism of rituximab also showed a complement-independent, proapoptotic effect mediated by cross-linking of CD20 (55), as well as antiproliferative and antisurvival effects that were mediated by inhibition of B cell receptors (56). Furthermore, many in vitro antitumor effects of complement-fixing antibodies on cancer cell lines were not reproduced in vivo (57). Complement activation promotes tumor growth. Considering that complement is not efficient in immune surveillance against cancer cells and that the main antitumor effect of monoclonal antibodies might not arise from complement activation, the data supporting an antitumor role for complement activation are scant. The question remains: If complement does not attack cancer cells, how does local complement activation and deposition of complement proteins affect tumors? To understand the consequence of complement activation inside tumors, it is helpful to reexamine the biological functions of complement activation products. C3b and its degradation products binding to CR1, CR2, and CR3 provide ligands and receptors for cell-cell and stroma-cell interactions in many physiologic and pathologic conditions. Complement activation generates C3a and C5a and MAC. The anaphylatoxin receptors C3aR and C5aR are G protein–coupled receptors present on many cell types, including lymphocytes, monocytes/macrophages, myeloid cells, hematopoietic stem cells, mesenchymal cells, and epithelial cells, including cancer cells. Anaphylatoxin receptor signaling has been studied extensively (58). Activation of C5aR promotes a range of responses depending on the cell type. Relevant to its role in cancer, C5aR activation generates prosurvival and antiapoptotic responses. For example, C5a binding to C5aR decreases apoptosis in neutrophils (59) and T cells (22), and increases cell proliferation in endothelial (60) and colon cancer cell lines (61). Activation of C3aR plays an important role in guiding collective cell migration (26) and epithelial-mesenchymal transition (62, 63), both important mechanisms in metastasis. In a sublytic density, MAC accumulation on the cell membrane promotes cell proliferation (64) and differentiation, inhibits apoptosis (10, 65), and protects cells against complement-mediated lysis (66). Markiewski et al. showed that the activation of the classical complement pathway inside implanted orthotopic tumors in mice enhanced tumor growth (67). Complement’s progrowth effect on tumors was C5a-dependent and was eliminated in C5aR-deficient mice and in WT mice treated with a C5aR antagonist. C5a modulates the immune response to tumors by acting as a chemotactic factor, increasing infiltration of myeloid-derived suppressor cells (MDSCs) and reducing the number of CD8+ cytotoxic T cells inside tumors. MDSCs are immature myeloid cells that increase in blood, bone marrow, and spleen of tumor-bearing mice and cancer patients (68, 69) and assist tumor cells in evading the antitumor immune response. MDSCs reduce proliferation and increase apoptosis in CD8+ T cells by generating ROS and reactive nitrogen species (70). Depletion of CD8+ T cells in mice eliminated the protective effect of complement deficiency against tumor growth. In summary, this study showed that the immunomodulatory effect of activated classical complement pathway inside tumors enhances tumor growth. The origin of complement proteins was the host, but activation of complement occurred inside the tumor microenvironment, and the final effect on the tumor was an indirect immunomodulatory effect mediated by MDSCs (Figure 2). Figure 2 Effect of complement activation in the tumor microenvironment. Activation of the complement system inside tumors releases C5a and C3a into the tumor microenvironment and promotes tumor growth. C5a attracts myeloid cell, including MDSCs, into the tumor. MDSCs then reduce cytotoxic T cell responses to the tumor by inducing apoptosis and inhibiting CD8+ TILs via generation of ROS and reactive nitrogen species and depletion of arginine. In melanoma, secretion of C3 by CD8+ TILs and complement activation in the vicinity of these cells reduce IL-10 production by TILs and inhibit their function. Some cancer cell types secrete complement proteins into the tumor microenvironment and initiate an autocrine loop that increases cell proliferation and promotes metastasis. The effect of complement activation on MDSCs, TILs, and cancer cells is mediated by the C5a and C3a receptors (C5aR and C3aR) on these cells. In a follow-up study, Nunez-Cruz et al. investigated complement’s role in tumorigenesis in a murine model of spontaneous ovarian cancer (71, 72). C3 or C5aR deficiency in these mice prevented the development of ovarian tumors, permitting no tumors or only small and poorly vascularized tumor formation (71). C3 deficiency was associated with a change in the immune profile of leukocytes infiltrating into the tumors, but C5aR deficiency reduced ovarian tumor size without altering the immune profile of infiltrating leukocytes. This result suggested the existence of a protumor effect of complement that was independent of its immunomodulatory effect. We investigated the effect of complement in murine models of ovarian cancer and confirmed activation of complement in the tumor microenvironment (73). However, complement proteins detected inside ovarian tumors originated not from the host, but from tumor cells themselves. Complement activation products were present even inside tumors implanted in C3-deficient mice lacking a functional complement system. Although orthotopic ovarian cancer tumors in C3-deficient mice reached to the same size as those in WT mice, reducing C3 or C5 production in cancer cells significantly reduced the tumor growth independent of the host’s complement sufficiency status. C3 synthesis can be detected in malignant epithelial cells originating from several different organs, particularly lung and ovary. Inhibiting synthesis of complement proteins in cancer cells altered the immune profile of leukocytes infiltrating into tumors, manifested by an increase in the number of CD8+ T cells and reduction in myeloid cells. However, immunomodulatory effect of complement inhibition was not the main mechanism responsible for the observed reduction in tumor growth. Inhibiting complement protein synthesis in cancer cells implanted in CD8+ T cell–deficient mice reduced tumor growth to the same magnitude as in WT mice. We investigated the possibility of an autocrine stimulation of cancer cells as a result of complement activation. Anaphylatoxin receptors are present on ovarian cancer cells, and stimulation of these receptors by C3a or C5a agonist peptides increased proliferation and invasiveness of ovarian cancer cells in vitro. Furthermore, knockdown of these receptors on cancer cells reduced growth of orthotopic ovarian tumors in mice. Our studies showed that local complement activation inside the tumor microenvironment enhances tumor growth via a direct autocrine effect on ovarian cancer cells increasing cell proliferation (Figure 2). In a murine model, Wang et al. reported another mechanism for the progrowth effect of complement activation in melanoma, showing that production of IL-10 by CD8+ tumor-infiltrating lymphocytes (TILs) is constitutively inhibited in an autocrine fashion by C3 originating from CD8+ TILs themselves, acting through C5aR and C3aR on the surface of these lymphocytes (74). C3aR and C5aR antagonists increased IL-10 production and activated CD8+ TILs that in turn reduce tumor growth. The IL-10–dependent antitumor activity of complement inhibitors in melanoma was independent of the PD-1/PD-L1 axis or MDSCs. This study provides evidence that local complement activation in the tumor microenvironment results in suppression of the immune response to melanoma by inhibiting CD8+ TIL function (Figure 2). The studies above describe different mechanisms by which complement activation in the tumor microenvironment can enhance tumor growth: (a) by altering the immune profile of tumor-infiltrating leukocytes, (b) by increasing cancer cell proliferation, and (c) by directly suppressing CD8+ TIL function. It is possible that different cancer types use different mechanisms to take advantage of ectopic complement activation inside tumors. For example, ovarian cancer cells synthesize a significant amount of complement proteins and initiate an autocrine loop resulting in increased cell proliferation by a direct effect of anaphylatoxins on cancer cells. Conversely, melanoma cells do not secrete complement proteins, and complement proteins produced by CD8+ TILs reduce their IL-10 production and antitumor activity. An important question remains whether complement activation has any role in malignant transformation of normal cells or only affects the expansion of already established malignant clones. Most available data are based on orthotopic murine models of ovarian cancer or mice genetically engineered to develop ovarian cancer by overexpression of oncogenes. These studies showed that complement promotes growth and expansion of malignant tumors. Bonavita et al. showed that complement promotes malignant transformation of cells exposed to chronic inflammation induced by chemical carcinogens (39). However, additional studies are required to dissect the effect of early versus late stages of complement activation on various stages of oncogenesis. Overexpression of CRPs on cancer cells If complement activation promotes tumor growth and oncogenesis, why are CRPs overexpressed on cancer cells? One would expect that cancer cells, under selective pressure, downregulate expression of CRPs to benefit from complement activation. To reconcile these seemingly counterintuitive observations, we put forward the following hypothesis: Anaphylatoxins and sublytic concentrations of MAC promote tumor growth, but higher concentrations of MAC have a tumoricidal effect. As a result, cancer cells benefit from early stages of complement activation and production of anaphylatoxins, but actively inhibit generation of MAC. Cancer cells reduce MAC concentration by overexpressing CD59, the most consistently overexpressed CRP on different cancer cells (75) and the most effective membrane regulatory protein against complement-mediated lysis (43, 76, 77), eliminating MAC from the cell surface through membrane vesiculation. Thus, from a therapeutic point of view, interventions that reduce complement activation or promote the generation of MAC inside tumors can be considered as logical options to counter the progrowth effect of complement on cancer. Complement activation in epithelial-mesenchymal transition Epithelial-mesenchymal transition (EMT) occurs in physiologic processes such as embryogenesis and organ development, and in pathologic conditions including tissue fibrosis and metastasis (78, 79). Complement participates in EMT in murine models of renal injury and fibrosis (62, 80, 81). We showed that complement activation inside tumors not only increases tumor growth but also enhances metastasis by promoting EMT in cancer cells. In ovarian cancer cells, the transcription factor TWIST1 upregulates C3 gene expression, generating C3a in the tumor microenvironment, which binds to C3aR on ovarian cancer cells. We further showed that C3aR signaling increases EMT and decreases E-cadherin expression in ovarian cancer cells via a Krüppel-like factor 5–dependent mechanism and promotes EMT and metastasis (63). In addition to promoting metastasis, EMT also induces resistance to complement-dependent cytotoxicity in lung cancer cells by increasing expression of CD59 (82). Inhibition or knockdown of CD59 restored sensitivity of cancer cells to complement-dependent lysis without altering the morphologic features or protein markers of EMT in these cells. Therapeutic potential of targeting complement activation in cancer Our understanding of the role of the complement system in cancer biology is evolving, changing our approach to the therapeutic use of reagents modifying the complement system. Traditional methods targeting cancer cells using antitumor antibodies to promote lysis of cancer cells by MACs require identification of tumor-specific antigens that either are expressed with a higher density on cancer cells than normal epithelial cells, or are only expressed on cancer cells. Antibodies against EGFR and CD20 are among the most successful therapeutic antibodies. Development of therapeutic antibodies was initially complicated by induction of an immune response to polyclonal antibodies developed in nonhuman hosts. Development of monoclonal murine antibodies; later, chimeric human-mouse antibodies; and recently, humanized antibodies (83) helps overcome this problem. However, a more important problem in harvesting complement-dependent cytotoxicity induced by therapeutic antibodies is overexpression of membrane CRPs by cancer cells that let cancer cells evade MAC-mediated cytolysis (43). As a result, blockade of membrane CRPs on cancer cells, alone or in conjunction with use of therapeutic antibodies, has been tried as another potential therapeutic strategy. Blocking CRPs reduces cancer cell proliferation in vitro (43) and tumor growth in mice (76). CD59 blocking antibodies or CD59 siRNA enhanced complement-mediated cytolysis induced by anti-EGFR monoclonal antibodies (trastuzumab and cetuximab) in human lung cancer cell lines (84). rILYd4, a recombinant protein inhibitor of CD59, increased sensitivity of malignant B cells to rituximab in vitro and in orthotopic murine models (85). Membrane CRPs are universally expressed, and an important theoretical complication of blocking CRPs is exposing normal cells to complement-dependent cytotoxicity. For example, CD59 and CD55 protect red blood cells against complement-induced hemolysis, and blocking CD59 might cause hemolysis. Interestingly, administration of rILYd4 in mice was not associated with significant increases in hemolysis (85). More recent studies showed a protumor effect of complement, and inhibition of complement activation in vitro or in murine models of cancer was investigated as a novel way to treat cancer. Understanding of the autocrine and paracrine effects of complement production and activation inside tumors versus its systemic immunomodulatory effect is not complete, but blocking complement activation or inhibiting C5aR and C3aR signaling inside tumors seems a reasonable approach. However, several questions and concerns regarding the therapeutic use of anticomplement reagents have not been addressed and require additional studies: Does systemic complement inhibition affect local production and activation of complement in the tumor microenvironment? Pharmacokinetic studies based on measurements of tissue concentration of various anticomplement reagents may resolve this issue, although the leakiness of tumor vasculature likely provides adequate tissue penetrance of these reagents. Does complement have a protumor effect in many or only in a few types of cancer? Recent studies showed that complement activation enhances growth of ovarian, cervical, and non–small-cell lung cancer and sarcoma, and deposition of complement proteins is detectable in more cancer cell types (Table 1). Which complement pathways are activated in cancer? Evidence supporting activation of classical, lectin, and alternative pathways in cancer exists. It is possible that in different types of cancer different pathways are functional. Therefore, it is more reasonable to target common complement proteins or receptors in antitumor therapies. What are the effects of early (C3a and C5a) versus late (MAC) complement activation end products on cancer cells? If higher concentrations of C3a or C5a promote, and denser MAC deposit reduces, tumor growth, developing bispecific inhibitory antibodies targeting C5aR (or C3aR) and CD59 simultaneously may increase the potency of the antitumor effect of complement therapy. Complement-dependent cytotoxicity has been considered an important component of the therapeutic benefit of monoclonal antibodies in malignant B cell disorders; however, the effects of complement activation on white blood cell dyscrasia have not been studied. A few reports point to a prognostic significance of expression of complement genes in leukemic blasts (86, 87). More comprehensive studies on the role of complement activation in leukemia and lymphoproliferative disorders might reveal possible therapeutic benefits of anticomplement reagents in these disorders. Eculizumab, a humanized anti-C5 monoclonal antibody, is currently available on the market and is used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. A single i.v. infusion of eculizumab blocks complement activation in plasma for 2–3 weeks (88, 89), but its potency and half-life in the interstitial tissue are unknown. Eculizumab blocks generation of C5a and MAC, but would not affect synthesis and secretion of complement proteins by cancer cells or C3a generation in the tumor microenvironment. Currently, no ongoing clinical trials are evaluating eculizumab in cancer patients; however, because of the clinical use of this reagent for other indications, we have a relatively clear picture of its side effect profile. Patients on eculizumab are at risk for developing infections with encapsulated microorganisms and should receive meningococcal vaccination before initiation of therapy. Lack of bone marrow suppression with eculizumab is a therapeutic advantage that can be used in designing clinical trials combining this reagent with chemotherapeutic reagents in cancer patients. In a few animal studies, C5aR antagonists, including PMX-53, have been shown to be effective in reducing tumor size in mice (67, 71), but this or similar reagents have not entered into clinical practice yet. Targeting C5aR rather than C5 or C3 might have the potential benefit of leaving opsonization and MAC generation intact. Intact opsonization of bacteria would reduce the risk of infectious complications in individuals undergoing treatment, and the generation of lytic concentrations of MAC might have a tumoricidal effect. On the other hand, targeting C5aR has the disadvantage of leaving other complement effector molecules, such as C3a, uninhibited. A potential advantage of using anticomplement reagents in cancer treatment is that they can be combined with traditional chemotherapies without increasing myelosuppression associated with chemotherapies; and combined with immune checkpoint inhibitors, because they have different targets. While checkpoint inhibitors increase proliferation of cytotoxic T cells, complement inhibitors decrease MDSCs infiltrating into the tumor microenvironment, reduce MDSC-induced T cell suppression, and enhance T cell function. Based on experiences collected with the clinical use of eculizumab, another advantage of complement inhibitors is their relatively few side effects. Any therapeutic use of anticomplement therapies in solid or liquid tumors should be carefully balanced with possible interference of complement inhibition with the efficacy of other antitumor reagents: (a) The outcome of combining anticomplement reagents with monoclonal antibodies (such as cetuximab, rituximab, or trastuzumab) may depend on the importance of complement-dependent cytotoxicity in the function of these antibodies. (b) Chimeric antigen receptor (CAR) T cell therapies depend on in vitro expansion and in vivo proliferation of T cells. Complement inhibition may decrease the proliferation of CAR T cells in vivo and may reduce their efficacy. Conclusions By mediating cell-cell and cell-stroma interactions, complement proteins have several immune and nonimmune functions in both plasma and the extravascular interstitial tissue. Activation of the complement system in the tumor microenvironment enhances tumor growth via different mechanisms. Anticomplement reagents might have a place in the therapeutic armamentarium against cancer and, because of their limited non-myelosuppressive side effects and nonoverlapping pharmacodynamics, could be combined with traditional chemotherapies or immunotherapies. Acknowledgments This work is supported in part by NIH grant CA177909 (to VAK). The author thanks Michael Kroll for his valuable comments. Footnotes Conflict of interest: The author has declared that no conflict of interest exists. Reference information: J Clin Invest. 2017;127(3):780–789. https://doi.org/10.1172/JCI90962. References Krem MM, Di Cera E. Evolution of enzyme cascades from embryonic development to blood coagulation. Trends Biochem Sci. 2002;27(2):67–74. View this article via: PubMed CrossRef Google Scholar Sjöberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol. 2009;30(2):83–90. View this article via: PubMed CrossRef Google Scholar Zipfel PF, Skerka C. 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April 22, 2018 12:00 PM
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Annu Rev Immunol. 2018 Apr 26;36:309-338. doi: 10.1146/annurev-immunol-042617-053245.
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Gilbert C FAURE
February 19, 2018 1:15 PM
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In the classical complement pathway, the C1 initiation complex binds to danger patterns on the surface of microbes or damaged host cells and triggers an immune response. Immunoglobulin G (IgG) antibodies form hexamers on cell surfaces that have high avidity for the C1 complex. Ugurlar et al. used cryo–electron microscopy to show how a hexamer of C1 complexes interacts with the IgG hexamer. Structure-guided mutagenesis revealed how C1 is activated to trigger an immune response.
Science , this issue p. [794][1]
[1]: /lookup/volpage/359/794?iss=6377
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Société Francaise d'Immunologie
December 18, 2017 6:53 AM
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Nat Commun. 2017 Dec 12;8(1):2078. doi: 10.1038/s41467-017-01526-z.
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Gilbert C FAURE
November 19, 2017 6:40 AM
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Gilbert C FAURE
September 20, 2017 2:32 AM
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Gilbert C FAURE
July 22, 2017 12:07 PM
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The innate immune response is evolutionary conserved among organisms. The complement system forms an important and efficient immune defense mechanism. It consists of plasma proteins that participate in microbial detection, which ultimately results in the production of various molecules with antimicrobial activity. Thioester-containing proteins (TEPs) are a superfamily of secreted effector proteins. In vertebrates, certain TEPs act in the innate immune response by promoting recruitment of immune cells, phagocytosis, and direct lysis of microbial invaders. Insects are excellent models for dissecting the molecular basis of innate immune recognition and response to a wide range of microbial infections. Impressive progress in recent years has generated crucial information on the role of TEPs in the antibacterial and anti-parasite response of the tractable model insect Drosophila melanogaster and the mosquito malaria vector Anopheles gambiae. This knowledge is critical for better understanding the evolution of TEPs and their involvement in the regulation of the host innate immune system.
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Société Francaise d'Immunologie
July 1, 2017 11:23 AM
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The complement system has been considered for a long time as a simple lytic system, aimed to kill bacteria infecting the host organism. Nowadays this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing a direct killing by C5b-9 membrane attack complex by triggering inflammatory responses with the anaphylatoxins C3a and C5a and helps the mounting of an adaptive immune response, involving antigen presenting cells, T- and B- lymphocytes. But it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Also examples will be discussed, where inadequate complement activation becomes a disease cause, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3G) and systemic lupus erythematosus (SLE). Age related macular degeneration (AMD) and cancer will be described as examples showing that complement contributes to a large variety of diseases, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.
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Gilbert C FAURE
April 4, 2019 3:11 PM
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The innate immune system comprises a cellular and a humoral arm. Humoral pattern recognition molecules include complement components, collectins, ficolins, and pentraxins. These molecules are involved in innate immune responses by recognizing microbial moieties and damaged tissues, activating complement, exerting opsonic activity and facilitating phagocytosis, and regulating inflammation. The long pentraxin PTX3 is a prototypic humoral pattern recognition molecule that, in addition to providing defence against infectious agents, plays several functions in tissue repair and regulation of cancer-related inflammation. Characterization of the PTX3 molecular structure and biochemical properties, and insights into its interactome and multiple roles in tissue damage and remodelling support the view that microbial and matrix recognition are evolutionarily conserved functions of humoral innate immunity molecules.
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January 10, 2019 2:41 PM
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Front Immunol. 2018 Dec 19;9:3046. doi: 10.3389/fimmu.2018.03046. eCollection 2018.Review...
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Société Francaise d'Immunologie
December 29, 2018 2:43 AM
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Via complement-mediated lysis When bacteria, such as Neisseria meningitidis, invade the body, they are attacked by immune proteins called complement proteins. Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or...
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Gilbert C FAURE
December 8, 2018 7:21 AM
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Pain. 2018 Nov 29. doi: 10.1097/j.pain.0000000000001449.[Epub ahead of print]...
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Gilbert C FAURE
November 19, 2018 4:07 AM
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Special Issue: 2018 International Complement Workshop
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LIGHTING
June 19, 2018 8:41 AM
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Gilbert C FAURE
April 22, 2018 2:27 AM
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Age-related macular degeneration (AMD) is a devastating neurodegenerative disease affecting millions worldwide. Complement activation, inflammation, and the loss of choroidal endothelial cells (CECs) have been established as key factors in both normal aging and AMD; however, the exact mechanisms for these events have yet to be fully uncovered. Herein, we provide evidence that the prototypic acute phase reactant, C-reactive protein (CRP), contributes to AMD pathogenesis. We discuss serum CRP levels as a risk factor for disease, immunolocalization of distinct forms of CRP in the at-risk and diseased retina, and direct effects of CRP on ocular tissue. Furthermore, we discuss the complement system as it relates to AMD pathophysiology, provide a model for the role of CRP in this disease, and outline current therapies being developed and tested to treat AMD patients.
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Gilbert C FAURE
January 1, 2018 2:20 AM
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Gilbert C FAURE
November 25, 2017 12:51 AM
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Complement is crucial to the immune response, but dysregulation of the system causes inflammatory disease. Complement is activated by three pathways: classical, lectin, and alternative. The classical and lectin pathways are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given the role of complement in disease, there is a requirement for inhibitors to control the initiating proteases. In this article, we show that a novel inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1. Gigastasin is a poor inhibitor of C1r. The inhibitor blocks the active sites of C1s and MASP-2, as well as the anion-binding exosites of the enzymes via sulfotyrosine residues. Complement deposition assays revealed that gigastasin is an effective inhibitor of complement activation in vivo, especially for activation via the lectin pathway. These data suggest that the cumulative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pathway than the more potent inhibition of only C1s of the classical pathway.
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Gilbert C FAURE
September 30, 2017 10:36 AM
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Gilbert C FAURE
July 31, 2017 1:36 PM
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The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of th
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Gilbert C FAURE
July 3, 2017 6:46 AM
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J Am Soc Nephrol. 2017 Jun 29. pii: ASN.2017010079. doi: 10.1681/ASN.2017010079. [Epub ahead of print]
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