Mucosal Immunity

The ATP-binding cassette (ABC) transporters P-glycoprotein (MDR1/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) play a crucial role in the translocation of a broad range of drugs; data about their expression and activity in lung...

New findings suggest how SARS-CoV-2 gets into respiratory tissue and how the body’s immune system may help it succeed.

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune ...

KEY POINTS Maternal T cells drive VUE responses; fetal immune cells drive infectious etiology. Clonal overlap between VUE subjects is minimal but common in placental infection. Contrary to placental infection, VUE T cells do not recognize common viral epitopes. Abstract During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis–placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses. Footnotes This work was supported by the National Institutes of Health (HD065987 to E.A.L.E., HD097843 to E.L.J. and R.C., and AI131566 to R.C. and C.M.G.), the Mayo Clinic Division of Anatomic Pathology (to S.E.K.), and the Mayo Clinic Center for Women's Health (to E.A.L.E.). The sequences presented in this article are available through immuneACCESS (clients.adaptivebiotech.com/pub/enninga-2020-ji) under accession number EALE2020JI. Received October 28, 2019. Accepted March 26, 2020. Copyright © 2020 by The American Association of Immunologists, Inc.

Fungi cover epithelial surfaces of the human body, engaging in many mutualistic interactions with the host and other microbiota such as the more prevalent bacteria. These interactions are shaped by multiple factors, including host physiology and immunity, as well as nutrient competition. The beneficial effects of fungal colonization for hosts include resistance to pathogens and tuning of the immune system. Although health benefits continue to be explored, recent studies have revealed expanded roles of fungi in human disease, including inflammatory disorders and specific cancers. The global burden of fungal infections is also expanding, with increased numbers of at-risk patients and increased resistance to limited antifungal drugs. More fungal research is needed to overcome these unmet needs. Fungi exist as single-celled yeast, multicellular molds, or dimorphic species occurring as both yeast and filamentous cells. Saccharomyces cerevisiae, Cryptococcus neoformans, and Candida and Malassezia spp. are frequently studied yeast, whereas Penicillium, Mucor, and Aspergillus are well-known molds. As with many microbiota, fungi are classically recognized for their roles as human-associated pathogens. Candidal bloodstream infections are the most common form of fungal invasive disease, affecting about 1 in 10,000 people in the United States. Globally, cryptococcal meningitis contributes to a substantial burden of disease, particularly in HIV-positive individuals. The paucity of available antifungal treatments contributes to the morbidity and mortality of fungal infections. Classes of antifungals include azoles (e.g., fluconazole), echinocandins, and amphotericin B. However, fluconazole is the only antifungal drug available in many parts of the world. Additionally, some fungal diseases can be difficult to diagnose because of nonspecific patient symptoms, invasive tissue sampling, specific culture conditions, and identification requiring sophisticated techniques. Recent studies have begun to explore how fungi are multifaceted in their potential to lead to beneficial as well as pathogenic outcomes for the host. Commensalism in the context of human fungi is exemplified by colonization resistance against pathogens. An example of a beneficial effect is the dominant human skin–associated Malassezia, which have adapted to their niche by making use of skin lipids as a nutrient, and then secreting antimicrobial products that deter bacterial pathogens (1). Another example of the importance of colonization resistance is Candida albicans commensalism in the gastrointestinal tract. In an evolutionary experiment, C. albicans strains acquired genetic mutations that enabled them to more stably colonize the mouse gastrointestinal tract. These evolved C. albicans strains provided protection against subsequent experimental challenges with different virulent fungi (C. albicans, Aspergillus fumigatus) and bacteria (Staphylococcus aureus, Pseudomonas aeruginosa) (2). However, these C. albicans strains evolved only in antibiotic-treated mice and were unable to stably colonize mice with endogenous gut bacteria, highlighting the genetic trade-offs of adaptation to the host and competition within mixed microbial communities. Complementary studies demonstrated that mutations in transcription factors that regulate morphology are key determinants of the gut commensal fitness of C. albicans (3). In addition to these direct host-microbial interactions, mouse gut colonization with C. albicans tuned host immunity, resulting in a systemic increase in fungal-specific T helper 17 (TH17) CD4+ T cells and interleukin-17 (IL-17)–responsive circulating neutrophils, which protected against more invasive bacterial and fungal, but not viral, infections (4). Ex vivo experiments showed that C. albicans elicited robust IL-17A and IL-22 responses from peripheral C. albicans– and A. fumigatus–specific TH17 CD4+ T cells from healthy human donors, demonstrating that C. albicans can modulate human immunity as well (5). Given the complexity of host-microbial interactions, any alteration in the host or microbiota can result in infections, ranging from chronic chromoblastomycosis of the skin, dermatophyte nail infections, and acute vaginal yeast infections to potentially fatal mucormycosis in diabetics, candidal sepsis, and disseminated aspergillosis. Deficiencies in human immunity provide insight into the host-microbiota interplay. For example, patients with advanced HIV infections suffer from specific opportunistic fungal infections such as cryptococcal meningitis, mucosal candidiasis, and Pneumocystis jirovecii pneumonia. In patients receiving a hematopoietic stem cell transplant, candidal bloodstream infections were preceded by blooms of intestinal Candida spp. with altered bacterial communities, which could be used as biomarkers to identify and alter medical management (6). Additionally, the specificity of host-fungal immune interactions is reflected in patients with genetically defined primary immunodeficiency syndromes such as chronic granulomatous disease, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), or caspase recruitment domain–containing protein 9 (CARD9) deficiency, each of which renders patients susceptible to a specific fungal infection. Other examples of host-specific fungal susceptibilities include mice deficient in the chemokine (C-X-C motif ) receptor 1 (Cxcr1) gene, which have defective neutrophil killing of Candida, decreased survival, and higher fungal burden. This phenotype is similar to that of disseminated candidiasis patients and healthy donors with the CXCR1-T276 allele who also demonstrate impaired neutrophil killing of Candida (7). Recurrent vulvovaginal candidiasis, a localized fungal infection, is estimated to affect more than 100 million women worldwide annually and has been linked with a functional variant in the SIGLEC15 (sialic acid–binding immunoglobulin-like lectin 15) gene (8). Expressed on immune cells, SIGLEC15 can bind C. albicans and induces IL-17A and interferon-γ (IFN-γ) production, suggesting a role in anti–C. albicans immune responses. Host susceptibility contributes to the development of more persistent or severe fungal infections—for example, from dermatophytes or penetrating wounds. Studies of other single-nucleotide polymorphism (SNP) variants in immune-related genes that correlate with increased susceptibility to mucosal or life-threatening fungal infections hold promise for the future development of precision medicine approaches for risk stratification and preventive treatment of patients at the highest risk for fungal disease. Inflammatory and autoimmune diseases are increasingly linked to alterations in fungal communities, particularly in genetically defined hosts. SNPs in CARD9 and CLEC7A (C-type lectin domain–containing 7A), which encodes Dectin-1, have been associated with inflammatory bowel diseases in humans. Dectin-1 is a C-type lectin receptor (CLR) that recognizes β-glucan in fungal cell walls and, through CARD9, signals to induce inflammatory mediators and TH1 and TH17 cell differentiation. Mice deficient in Dectin-1 had more severe experimentally induced colitis with increased C. tropicalis burden, and a SNP in human CLEC7A is associated with more severe ulcerative colitis (9). Similarly, Crohn's disease patients have higher relative abundances of intestinal Malassezia compared with healthy controls, and oral gavage of Malassezia demonstrated worsening of experimental colitis in mice, again through activation of CARD9 signaling and downstream TH1 and TH17 cell polarization (10). Genetic ablation of CX3CR1+ mononuclear phagocytes, which express antifungal CLRs, also exacerbated experimental colitis in mice. Furthermore, a missense mutation in CX3CR1 in Crohn's disease patients has been associated with reduced immunoglobulin G (IgG) responses to fungi (11). These and other studies suggest that inflammatory diseases may result from host-fungal imbalances. Although bacteria and viruses have been implicated in cancer, fungi typically have not been. Histologic observations revealed higher amounts of intratumoral fungi, particularly of Malassezia, infiltrating human pancreatic ductal adenocarcinomas (PDAs). Further investigation of mouse models of PDA demonstrated fungal translocation from the intestinal tract into the pancreas, increased burden of Malassezia accelerated PDA progression, and antifungal treatment slowed pancreatic cancer growth (12). The complement cascade integrates immune recognition and fungal killing with tumor development by stimulating proinflammatory pathways. Human tissue expression of mannose-binding lectin (MBL), which activates the complement cascade, was associated with worse survival in PDA patients. Similarly, PDA progression in mice depended on Malassezia stimulation of MBL, linking fungi, inflammation, and tumorigenesis. This study has prompted researchers to reconsider the potential relationships between fungi and broader human diseases. Candida auris epitomizes the gravest concerns about an emerging fungal pathogen because it has evolved resistance to all classes of antifungal drugs, particularly azoles. Numerous countries have reported active outbreaks, with increasing cases of C. auris bloodstream infections. The high prevalence of resistance renders these infections difficult to treat, with resultant high mortality. Over the past decade, four distinct strains of C. auris have emerged independently on different continents. The origin of C. auris as a human pathogen has remained a mystery since it was first identified in 2009. The propensity of C. auris to colonize human skin for a long time, which is an atypical feature for non-auris Candida species, is of substantial concern because shedding from patients into the environment facilitates transmissions within health care facilities (13). The emergence of a new human fungal pathogen points to urgent unmet medical needs for new antifungal drugs and environmental disinfectants, genomic datasets that include fungal sequences to map global fungal diversity, and a coordinated global health response. Aspergillus spores are frequently inhaled into lungs but cause disease only in some people. PHOTO: THE NATURAL HISTORY MUSEUM, LONDON/SCIENCE SOURCE Investigations into the role of fungi in human health and disease are challenging. Despite a myriad of bacteria, fungi, and viruses existing together in and on humans, researchers tend to focus on a few microbial species because they are more tractable to study. Diverse culture conditions or inclusion of metabolically distinct forms of dimorphic fungi (3) may reveal different functions and interactions. In vivo systems also have limitations. For example, conventional laboratory mice have a lower fungal burden and different immune profiles than those of wild-type mice (14). Additionally, adaptation to stress—induced by, for example, culture conditions, passaging through mammalian hosts, antifungal pressures, high temperatures, or acidic pH—can lead to alterations in morphology, fungal capsule, and cell wall components. This can result in evasion or triggering of host immunity and radically altered genomes in fungal cells. Genomic plasticity in fungi, including loss of heterozygosity, copy number variation, and aneuploidy, underscores the importance of incorporating metagenomic analyses into studies of fungal community adaptation to different niches (15). Fungal research is an area of considerable potential. This includes understanding how fungi are beneficial to human health and mining the multiple compounds produced by fungi that may benefit clinical medicine (for example, penicillin is derived from the fungal species Penicillium spp.). The emergence of multidrug-resistant C. auris has been postulated to be due in part to rising temperatures and to the widespread use of azoles in agriculture and in the clinic. Because these pressures on host-microbial homeostasis are likely to persist and evolve, the development of new antifungal drugs is critical to counteract outbreaks from existing and future pathogens. Advances in technology, such as targeted CRISPR-Cas9–mediated gene deletion for fungal mutagenesis, can provide precise tools for testing genetic hypotheses and elucidating fungal pathophysiology. Further advances will continue to improve our understanding of how fungi affect human health and disease. http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License. References and Notes ↵ G. Wu et al., PLOS Genet. 11, e1005614 (2015).OpenUrlCrossRefPubMed ↵ G. H. W. Tso et al., Science 362, 589 (2018). ↵ J. N. Witchley et al., Cell Host Microbe 25, 432 (2019).OpenUrl ↵ T. Y. Shao et al., Cell Host Microbe 25, 404 (2019).OpenUrl ↵ P. Bacher et al., Cell 176, 1340 (2019).OpenUrlCrossRef ↵ B. Zhai et al., Nat. Med. 26, 59 (2020).OpenUrlCrossRefPubMed ↵ M. Swamydas et al., Sci. Transl. Med. 8, 322ra10 (2016). ↵ M. Jaeger et al., Sci. Transl. Med. 11, eaar3558 (2019). ↵ I. D. Iliev et al., Science 336, 1314 (2012). ↵ J. J. Limon et al., Cell Host Microbe 25, 377 (2019).OpenUrlCrossRef ↵ I. Leonardi et al., Science 359, 232 (2018). ↵ B. Aykut et al., Nature 574, 264 (2019).OpenUrlCrossRef ↵ B. R. Jackson et al., J. Fungi 5, 58 (2019).OpenUrlCrossRef ↵ S. P. Rosshart et al., Science 365, eaaw4361 (2019). ↵ A. Forche et al., mBio 2, e00129 (2011).OpenUrlCrossRefPubMed Acknowledgments: The authors are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K.) and the National Human Genome Research Institute (J.A.S.).

The lungs are ground zero for COVID-19, but blood clots may play a surprisingly big role in severe illness. On rounds in a 20-bed intensive care unit (ICU) one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. “They are all COVID positive.”

As the number of confirmed cases of COVID-19 surges past 2.2 million globally and deaths surpass 150,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, its reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.  “[The disease] can attack almost anything in the body with devastating consequences,” says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. “Its ferocity is breathtaking and humbling.” 

Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? What explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? “Taking a systems approach may be beneficial as we start thinking about therapies,” says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP)....

Cyclically, during the day, increased permeability of the intestinal epithelial barrier,
allowing nutrient uptake, must be compensated for, to achieve increased protection
against potentially harmful components.

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Abstract
Dynamic interactions between the gastrointestinal epithelium and the mucosal immune system normally contribute to ensuring intestinal homeostasis and optimal immunosurveillance, but destabilisation of these interactions in genetically predisposed individuals can lead to the development of chronic inflammatory diseases. Ulcerative colitis is one of the main types of inflammatory diseases that affect the bowel, but its pathogenesis has yet to be completely defined. Several genetic factors and other inflammation-related genes are implicated in mediating the inflammation and development of the disease. Some susceptibility loci associated with increased risk of ulcerative colitis are found to be implicated in mucosal barrier function. Different biomarkers that cause damage to the colonic mucosa can be detected in patients, including perinuclear ANCA, which is also useful in distinguishing ulcerative colitis from other colitides. The choice of treatment for ulcerative colitis depends on disease severity. Therapeutic strategies include anti-tumour necrosis factor alpha (TNF-α) monoclonal antibodies used to block the production of TNF-α that mediates intestinal tract inflammation, an anti-adhesion drug that prevents lymphocyte infiltration from the blood into the inflamed gut, inhibitors of JAK1 and JAK3 that suppress the innate immune cell signalling and interferons α/β which stimulate the production of anti-inflammatory cytokines, as well as faecal microbiota transplantation. Although further research is still required to fully dissect the pathophysiology of ulcerative colitis, understanding its cellular pathology and molecular mechanisms has already proven beneficial and it has got the potential to identify further novel, effective targets for therapy and reduce the burden of this chronic disease.

Keywords: Ulcerative colitis, Cytotoxic T-lymphocyte antigen 4 (CTLA4), IL-10, Tumour necrosis factor alpha (TNF-α), Faecal microbiota transplantation

Summary Pulmonary sarcoidosis is characterized by an exaggerated CD4+ T cell response and formation of non‐necrotizing granulomas. Tumour necrosis factor α (TNF‐α) is regarded as crucial for granul...

Author summary Microfold (M) epithelial cells are important for the onset of infections and induction of immune responses in many mucosal diseases. We extended a human in vitro M cell model to apical infections, expression of fluorescent host and microbial reporters and real-time fluorescence...