Host Cell & Pathogen Interactions
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Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children

Toll-like receptors (TLRs) form an essential part of the innate immune system, which plays a fundamental role in rapidly and effectively controlling infections and initiating adaptive immunity.
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Host Cell & Pathogen Interactions
Strategies of Microbial Virulence and Host Defense
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A Bacterial Two Hit Combo Against Cancer

A Bacterial Two Hit Combo Against Cancer | Host Cell & Pathogen Interactions | Scoop.it

An engineered strain of Salmonella has been shown to prevent the spread of tumors in mice without causing a harmful systemic infection.


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Antigen processing and immune regulation in the response to tumours

Antigen processing and immune regulation in the response to tumours | Host Cell & Pathogen Interactions | Scoop.it
The MHC class I and II antigen processing and presentation pathways display peptides to circulating CD8+ cytotoxic and CD4+ helper T cells respectively to enable pathogens and transformed cells to b

Via Gilbert C FAURE
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Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection | Host Cell & Pathogen Interactions | Scoop.it
JAK1 mediates intracellular signalling from multiple cytokine receptors. Here, Elettoet al.
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The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity

The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity | Host Cell & Pathogen Interactions | Scoop.it
The Hippo pathway, known to be tumor suppressive, is surprisingly found to have a
role in suppressing anti-tumor immune responses. Loss of the LATS1/2 kinases results
in the induction of innate and adaptive immune responses that reduce tumor growth
and improves vaccine efficacy.

Via Gilbert C FAURE
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Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody–producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen–experienced IgD–CD38+/–CD19+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-α but also, the less frequent APRIL-/ mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9–induced aberrant expression of APRIL in tonsillar GC B cells.
Via Gilbert C FAURE
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Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition*

Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition* | Host Cell & Pathogen Interactions | Scoop.it
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The inflammasome: Friend or foe in Chlamydia infection?

The inflammasome: Friend or foe in Chlamydia infection? | Host Cell & Pathogen Interactions | Scoop.it
RT @BiomedJ: The inflammasome: Friend or foe in #Chlamydia infection? https://t.co/dlUiOqOVWs #immunology https://t.co/r9dcUofjtX
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3D Map of Apoptosome in Action Offers Better Understanding of Cell Death

3D Map of Apoptosome in Action Offers Better Understanding of Cell Death | Host Cell & Pathogen Interactions | Scoop.it

It appears inside doomed cells when bidden, like a creature from a horror film: a seven-pronged, wheel-shaped structure that orders its minions to go on a killing spree. They obey, snipping away at critical parts of a cell until it implodes. The command structure is called the wheel of death, or, if you’re a scientist, the apoptosome.

 

But the process, called programmed cell death, or apoptosis—from the Greek words for leaves falling from a tree—is a normal part of life. Cells die in an orderly fashion so that during development, we’re not born with webbed hands, for example, and during adulthood we have a protective layer of dead skin cells on top of live ones. Apoptosis is perhaps best known for its role in cancer, either killing cancer cells as they start to proliferate or failing to kill them.

 

At the center of all this destruction is the apoptosome, the cellular structure that facilitates programmed cell death. Scientists knew it existed decades ago, and over time they have slowly, painstakingly, built models of its structure to better understand its function. In October 2016, a team led by Christopher Akey, a Boston University School of Medicine professor of physiology and biophysics, revealed the most detailed three-dimensional model of the apoptosome to date.

 

The model, published in the journal eLife, answers some questions and raises others. Ultimately, a better understanding of how cell death occurs may lead to treatment options that can enhance or suppress the process.

 

“The apoptosome was discovered more than 20 years ago, but now we have a much better idea of how it works,” says Yale School of Medicine postdoctoral associate Tat Cheung Cheng, lead author on the eLife paper and a former postdoctoral fellow under Akey. “This lays groundwork for future drug development.”


Via Dr. Stefan Gruenwald
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Interferon lambda 4 expression is suppressed by the host during viral infection

Interferon lambda 4 expression is suppressed by the host during viral infection | Host Cell & Pathogen Interactions | Scoop.it
Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFNλ1, IFNλ2, and IFNλ3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepatitis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that introduces a premature stop codon. We performed a molecular and biochemical characterization of IFNλ4 to determine its role and regulation of expression. We found that IFNλ4 exhibits similar antiviral activity to IFNλ3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFNλ4 expression, suggesting that immune function is dependent on other IFNL family members.
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Innate immune responses in the ageing lung - Boe - 2016 - Clinical & Experimental Immunology - Wiley Online Library

Innate immune responses in the ageing lung - Boe - 2016 - Clinical & Experimental Immunology - Wiley Online Library | Host Cell & Pathogen Interactions | Scoop.it

Via Gilbert C FAURE
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The Human Virome 

The Human Virome  | Host Cell & Pathogen Interactions | Scoop.it
Some of our resident viruses may be beneficial.

Via Ed Rybicki
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Ed Rybicki's curator insight, November 1, 2016 11:23 AM
EXCELLENT article.
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Epigenetics: Cancer and Beyond | The New York Academy of Sciences

Epigenetics: Cancer and Beyond | The New York Academy of Sciences | Host Cell & Pathogen Interactions | Scoop.it
Check out this eBriefing from the Academy’s archive on #epigenetics, #cancer and beyond. https://t.co/RaXhN7fa5S
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Cells fight back against virus factories

Cells fight back against virus factories | Host Cell & Pathogen Interactions | Scoop.it
This week I've been talking to first year students about cell biology, discussing how much the environment of the cell varies from one site to another within the cell. Viruses "know" this and much virus replication is localized at particular sites within the cell, not just occurring haphazardly. The first example of this is to…

Via Chris Upton + helpers
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Cocktail of bacteria-killing viruses prevents cholera infection in animal models

Cocktail of bacteria-killing viruses prevents cholera infection in animal models | Host Cell & Pathogen Interactions | Scoop.it

Oral administration of a cocktail of three viruses, all of which specifically kill cholera bacteria, prevents infection and cholera-like symptoms in animal model experiments, report scientists from Tufts University School of Medicine (TUSM) and the Sackler School of Graduate Biomedical Sciences at Tufts inNature Communications on Feb. 1. The findings are the first to demonstrate the potential efficacy of bacteria-killing viruses—known as bacteriophages, or phages—as an orally administered preventive therapy against an acute gastrointestinal bacterial disease.

 

“While phage therapy has existed for decades, our study is proof-of-principle that it can be used to protect against infection and intervene in the transmission of disease,” said senior study author Andrew Camilli, Ph.D., Howard Hughes Medical Institute Investigator and professor of molecular biology and microbiology at TUSM. “We are hopeful that phages can someday be a tool in the public health arsenal that helps decrease the global burden of cholera, which affects up to four million people around the world each year.”

 

In previous work, Camilli and colleagues searched for phages that are specific for Vibrio cholerae, the bacterium that causes cholera—a potentially lethal infectious disease marked by severe diarrhea and dehydration. While phages that kill V. cholerae are abundant in nature, the team identified three strains that uniquely retained the ability to kill V. cholerae within the small intestine, the site of infection in humans. These phages function by targeting bacterial surface receptors normally involved in infectiousness, making them ideal therapeutic candidates—to develop resistance, cholera bacteria must acquire mutations in these receptors, which cause the bacteria to become less infectious.


Via Dr. Stefan Gruenwald
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Ed Rybicki's curator insight, February 13, 5:08 AM
While this great, it is a modern vindication of something no less a person that the co-discoverer of phages himself, Felix d'Herelle, advocated as a cure for dysentery - and put into practice in India in the 1920s, apparently (https://rybicki.wordpress.com/2015/02/17/happy-centenary-phages/). He was also the godfather of work done at the Eliava Institute in Georgia, which really laid the foundation of phage therapy.
Ed Rybicki's comment, February 13, 5:09 AM
Thanks! Great stuff.
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Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner | Host Cell & Pathogen Interactions | Scoop.it
National Academy of Sciences

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10 Mysteries of the Human Microbiome Revealed

10 Mysteries of the Human Microbiome Revealed | Host Cell & Pathogen Interactions | Scoop.it
Your body hosts trillions of microbes—mainly bacteria, fungi, and viruses. That's (mostly) a good thing.
Via Gilbert C FAURE
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Research Spotlight: New Frontiers in Cellular Therapies – 360 Degrees of Immuno-oncology - Dana-Farber Cancer Institute | Boston, MA

Research Spotlight: New Frontiers in Cellular Therapies – 360 Degrees of Immuno-oncology - Dana-Farber Cancer Institute | Boston, MA | Host Cell & Pathogen Interactions | Scoop.it
New Frontiers in Cellular Therapies: The field of immuno-oncology has recently exploded with novel cellular therapies that elegantly exploit the tumor-antigen recognition and cytotoxic potential of T cells.
Via Krishan Maggon , Gilbert C FAURE
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Proliferating Helper T Cells Require Rictor/mTORC2 Complex to Integrate Signals from Limiting Environmental Amino Acids*

Proliferating Helper T Cells Require Rictor/mTORC2 Complex to Integrate Signals from Limiting Environmental Amino Acids* | Host Cell & Pathogen Interactions | Scoop.it
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The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses

The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses | Host Cell & Pathogen Interactions | Scoop.it
Author Summary The extensive investigation of interferon antagonism mediated by Ebola virus (EBOV) over the last 16 years resulted in identification of two interferon inhibiting domains (IIDs) located in the VP24 and VP35 proteins of the virus and...
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Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication

Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication | Host Cell & Pathogen Interactions | Scoop.it
Understanding the host immune response to vaginal exposure to RNA viruses is required to combat sexual transmission of this class of pathogens. In this study, using lymphocytic choriomeningitis virus (LCMV) and Zika virus (ZIKV) in wild-type mice, we show that these viruses replicate in the vaginal mucosa with minimal induction of antiviral interferon and inflammatory response, causing dampened innate-mediated control of viral replication and a failure to mature local antigen-presenting cells (APCs). Enhancement of innate-mediated inflammation in the vaginal mucosa rescues this phenotype and completely inhibits ZIKV replication. To gain a better understanding of how this dampened innate immune activation in the lower female reproductive tract may also affect adaptive immunity, we modeled CD8 T cell responses using vaginal LCMV infection. We show that the lack of APC maturation in the vaginal mucosa leads to a delay in CD8 T cell activation in the draining lymph node and hinders the timely appearance of effector CD8 T cells in vaginal mucosa, thus further delaying viral control in this tissue. Our study demonstrates that vaginal tissue is exceptionally vulnerable to infection by RNA viruses and provides a conceptual framework for the male to female sexual transmission observed during ZIKV infection.
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How Epstein-Barr Virus Hijacks B Cells To Cause Blood Cancer | The Scientist Magazine®

How Epstein-Barr Virus Hijacks B Cells To Cause Blood Cancer | The Scientist Magazine® | Host Cell & Pathogen Interactions | Scoop.it
Scientists describe a mechanism by which EBV controls the expression of two genes, leading B cells to replicate out of control and avoid apoptosis.

Via Gilbert C FAURE
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Gilbert C FAURE's curator insight, November 19, 2016 2:45 AM
C. Wood et al., "MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs," Science, 354:857-61, 2016.
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Mutational signatures associated with tobacco smoking in human cancer

Mutational signatures associated with tobacco smoking in human cancer | Host Cell & Pathogen Interactions | Scoop.it
We have known for over 60 years that smoking tobacco is one of the most avoidable risk factors for cancer. Yet the detailed mechanisms by which tobacco smoke damages the genome and creates the mutations that ultimately cause cancer are still not fully understood. Alexandrov et al. examined mutational signatures and DNA methylation changes in over 5000 genome sequences from 17 different cancer types linked to smoking (see the Perspective by Pfeifer). They found a complex pattern of mutational signatures. Only cancers originating in tissues directly exposed to smoke showed a signature characteristic of the known tobacco carcinogen benzo[ a ]pyrene. One mysterious signature was shared by all smoking-associated cancers but is of unknown origin. Smoking had only a modest effect on DNA methylation.

Science , this issue p. [618][1]; see also p. [549][2]

[1]: /lookup/doi/10.1126/science.aag0299
[2]: /lookup/doi/10.1126/science.aal2114

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This new compound could help kill up to a quarter of all cancer types targeting Mcl1

This new compound could help kill up to a quarter of all cancer types targeting Mcl1 | Host Cell & Pathogen Interactions | Scoop.it

Scientists have developed a new compound that's effective at inhibiting the growth of multiple types of cancer models in the lab – slowing as many as a quarter of all known types of cancer. The molecule, called S63845, works by blocking the protein MCL1, which many different types of cancer cells rely on to grow. And without access to MCL1, the cancer cells die off.

 

The discovery could help researchers fight blood cancers such as acute myeloid leukemia, lymphoma, and multiple myeloma. Solid tumors – including melanoma and cancers of the lung and breast – could also see new treatments.

 

"MCL1 (a bcl2 family member) is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body," says one of the team, Guillaume Lessene from the Walter and Eliza Hall Institute in Australia. "Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival."

 

Cancerous cells are difficult for the body's immune system to kill, because they can quickly evolve and spread faster than our defences can keep up, and can also evade what's called apoptosis – a form of programmed cell death.

 

Blasting them with chemotherapy drugs or radiation can be an effective way to combat cancer cells, but these techniques usually take healthy cells along with them, and cause debilitating side effects.

 

What makes S63845 so promising is that, in addition to cutting off cancer's life support system, it can be given at doses that don't harm normal cells, the team suggests. The compound is the latest development in a new class of anti-cancer drugs called BH3 mimetics, which target a family of proteins that cancers rely on to sidestep and resist programmed cell death.

 

"BH3 mimetics inhibit a group of proteins known as the 'pro-survival BCL-2 proteins'," says Lessene. "MCL1 is a member of this protein family, and inhibiting it activates the process of programmed cell death."

It's worth pointing out that research is still at a pre-clinical stage, and the researchers need to run further tests on the compound before turning it into a drug that can be taken safely by human patients. But the early signs are very encouraging.


Via Dr. Stefan Gruenwald
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How to knock out herpesvirus RNA transport — with applications from cold sores to cancer

How to knock out herpesvirus RNA transport — with applications from cold sores to cancer | Host Cell & Pathogen Interactions | Scoop.it
A new approach has been developed to combat diseases caused by herpesvirus infections, including everything from cold sores to cancer.

 

Researchers at the University of Leeds have discovered a way to prevent herpesviruses hijacking important pathways in cells which are required for the virus to replicate and cause disease.

Professor Adrian Whitehouse from the School of Molecular Biology and Astbury Centre for Structural Molecular Biology at the University led the five year study, the results of which are published today in the journal Nature Microbiology.

 

Prof Whitehouse said: "We've spent several years demonstrating that a protein found in all herpesviruses, recruits a protein complex in the host cell, called human TREX, to help stabilise and transport herpesvirus RNAs out of a cell's nucleus so they are turned into viral proteins. "Now we have identified a compound which can disrupt this essential virus-host cell interaction which in turn prevents herpesviruses replicating and producing infectious particles."

 

The approach the researchers used was unique as it targeted the enzyme activity of a key component of the cellular human TREX complex, known as UAP56.  Inhibiting t his activity prevented the remodelling of the human TREX complex which stopped the interaction with the viral protein.

 

The project is a collaboration between virologists led by Professor Whitehouse and a team of chemists led by Dr Richard Foster also from the University of Leeds. Dr Foster's team performed a virtual screen of thousands of compounds to identify potential inhibitors. These were then tested for their ability to stop herpesvirus replication without damaging the host cell.


Via Dr. Stefan Gruenwald
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Emily's comment, November 21, 2016 12:57 AM
Look great
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Enrichment of Phosphatidylethanolamine in Viral Replication Compartments via Co-opting the Endosomal Rab5 Small GTPase by a Positive-Strand RNA Virus

Enrichment of Phosphatidylethanolamine in Viral Replication Compartments via Co-opting the Endosomal Rab5 Small GTPase by a Positive-Strand RNA Virus | Host Cell & Pathogen Interactions | Scoop.it
Positive-strand RNA viruses build extensive membranous replication compartments to support replication and protect the virus from antiviral responses by the host. These viruses require host factors and various lipids to form viral replication complexes (VRCs). The VRCs built by Tomato bushy stunt virus (TBSV) are enriched with phosphatidylethanolamine (PE) through a previously unknown pathway. To unravel the mechanism of PE enrichment within the TBSV replication compartment, in this paper, the authors demonstrate that TBSV co-opts the guanosine triphosphate (GTP)-bound active form of the endosomal Rab5 small GTPase via direct interaction with the viral replication protein. Deletion of Rab5 orthologs in a yeast model host or expression of dominant negative mutants of plant Rab5 greatly decreases TBSV replication and prevents the redistribution of PE to the sites of viral replication. We also show that enrichment of PE in the viral replication compartment is assisted by actin filaments. Interestingly, the closely related Carnation Italian ringspot virus, which replicates on the boundary membrane of mitochondria, uses a similar strategy to the peroxisomal TBSV to hijack the Rab5-positive endosomes into the viral replication compartments. Altogether, usurping the GTP-Rab5–positive endosomes allows TBSV to build a PE-enriched viral replication compartment, which is needed to support peak-level replication. Thus, the Rab family of small GTPases includes critical host factors assisting VRC assembly and genesis of the viral replication compartment.

Via Suayib Üstün, Guogen Yang
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