The ability to recognize invading viral pathogens and to distinguish their components from those of the host cell is critical to initiate the innate immune response. The efficiency of this detection is an important factor in determining the susceptibility of the cell to viral infection. Innate sensing of viruses is, therefore, an indispensable step in the line of defense for cells and organisms. Recent discoveries have uncovered novel sensors of viral components and hallmarks of infection, as well as mechanisms by which cells discriminate between self and non-self. This review highlights the mechanisms used by cells to detect viral pathogens in the cytosol, and recent advances in the field of cytosolic sensing of viruses.
In a recent study, Rochester scientists made two important contributions to DNA damage research. First, though scientists could previously point to an association between DNA damage and aging, the Rochester group has demonstrated a causal relationship between reduced DNA damage and extended lifespan. Second, the researchers have identified a cellular factor—an enzyme called topoisomerase 2, or Top2, implicated in DNA damage—that can be targeted to reduce that damage. The findings are published in the journal Aging.
Pathogenic Versus Commensal Tumor Viruses Another way to look at infectious carcinogens is whether or not a tumor virus is a rare or a common human infection. Commensal viruses are common, inapparent infections that do not usually cause symptoms or disease in the host.
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.
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
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...
Via Gilbert C FAURE
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.
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. ; see also p. 
On occasion, a virus may jump from one host species to another and adapt to the new host. Such cross-species transmission happens more often than expected, according to new research, and it may play a much bigger role in virus evolution than previously thought.
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.
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
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.”
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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