The virome contains the most abundant and fastest mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, ...and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our coevolved virome, a concept with profound implications for understanding health and disease.
Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the ...essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.
IFN-γ activates cells to restrict intracellular pathogens by upregulating cellular effectors including the p65 family of guanylate-binding proteins (GBPs). Here we test the role of Gbp1 in the ...IFN-γ-dependent control of T. gondii in the mouse model. Virulent strains of T. gondii avoided recruitment of Gbp1 to the parasitophorous vacuole in a strain-dependent manner that was mediated by the parasite virulence factors ROP18, an active serine/threonine kinase, and the pseudokinase ROP5. Increased recruitment of Gbp1 to Δrop18 or Δrop5 parasites was associated with clearance in IFN-γ-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Δrop18 mutants in IFN-γ-activated macrophages was reverted in Gbp1(-/-) cells, and decreased virulence of this mutant was compensated in Gbp1(-/-) mice, which were also more susceptible to challenge with type II strain parasites of intermediate virulence. These findings demonstrate that Gbp1 plays an important role in the IFN-γ-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense.
Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient ...deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the ...host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon- and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host.
Mammals are defined by their metagenome, a combination of host and microbiome genes. This knowledge presents opportunities to further basic biology with translation to human diseases. However, the ...now-documented influence of the metagenome on experimental results and the reproducibility of in vivo mammalian models present new challenges. Here we provide the scientific basis for calling on all investigators, editors and funding agencies to embrace changes that will enhance reproducible and interpretable experiments by accounting for metagenomic effects. Implementation of new reporting and experimental design principles will improve experimental work, speed discovery and translation, and properly use substantial investments in biomedical research.
STAT1-Dependent Innate Immunity to a Norwalk-like Virus Karst, Stephanie M.; Wobus, Christiane E.; Lay, Margarita ...
Science (American Association for the Advancement of Science),
03/2003, Volume:
299, Issue:
5612
Journal Article
Peer reviewed
Norwalk-like caliciviruses (Noroviruses) cause over 90% of nonbacterial epidemic gastroenteritis worldwide, but the pathogenesis of norovirus infection is poorly understood because these viruses do ...not grow in cultured cells and there is no small animal model. Here, we report a previously unknown murine norovirus. Analysis of Murine Norovirus 1 infection revealed that signal transducer and activator of transcription 1-dependent innate immunity, but not T and B cell-dependent adaptive immunity, is essential for norovirus resistance. The identification of host molecules essential for murine norovirus resistance may provide targets for prevention or control of an important human disease.
Microbial villages shape viral infections
Viruses infecting the intestinal tract, such as noroviruses and rotaviruses, are major human pathogens. Despite facing an extreme environment within their ...hosts, which includes pH gradients, digestive enzymes, and the billions of microbes that inhabit human guts, these viruses somehow manage to survive and often thrive. Pfeiffer and Virgin review the complex microbial encounters that occur between enteric viruses and gut microbiota. Trans-kingdom interactions (that is, between viruses, bacteria, archaea, helminthes, fungi, and phage) are particularly important in shaping the course of a viral infection and the ensuing host immune response.
Science
, this issue p.
10.1126/science.aad5872
BACKGROUND
Viruses that infect the mammalian gastrointestinal tract have intimate relationships with the host, as well as members of the complex community of microbes that inhabit the intestine. The mammalian intestine contains the highest density of microbes in the body. These microbes, collectively referred to as the intestinal microbiota, include bacteria, archaea, fungi, viruses, and eukaryotes. Emerging data indicate that enteric viruses regulate, and are regulated by, these other microbes through a series of processes termed “transkingdom interactions.” Recent advances have shed light on the nature and importance of these transkingdom interactions for enteric virus replication, transmission, and disease.
ADVANCES
The study of enteric virus pathogenesis has traditionally focused on viral virulence genes of classical pathogens and host immunity to these agents. Recent analysis of the viruses present in the intestine has revealed a dynamic and diverse taxonomic intestinal viral world (the enteric virome) featuring, in addition to recognized enteric viral pathogens, many new viruses and new relationships between known viral types and disease. We now know that enteric viral infection must be considered in light of the fact that viruses are part of a complex milieu of microbes and microbial products that directly and indirectly regulate viral pathogenesis. Thus, interactions of enteric viruses with other microbes are increasingly recognized as critical to viral infectivity, disease, and control. Studies leveraging the simple paradigm of examining enteric viruses in the intestine after natural oral infection have driven the field forward. It is now clear that members of the intestinal microbiome promote replication and transmission of enteric viruses from four different families: noroviruses, picornaviruses, retroviruses, and reoviruses. Therefore, the standard reductionist approach of understanding the pathogenesis of, and immunity to, viral infection in the context of a single virus interacting with a single host is too limited to capture the full range of relevant pathogenic mechanisms. This simple concept has broad implications for prevention and therapy of viral infections of great medical importance.
OUTLOOK
Despite recent rapid advances, there are still major gaps in our understanding of transkingdom control of enteric virus replication, pathogenesis, and transmission. Recognition of the important impact of the bacterial microbiota has advanced more rapidly than for any other component of the intestinal microbiota. A particular challenge for studies to comprehensively identify viruses within the enteric virome is their diversity and extreme sequence variability. A key direction for the field is to identify functional relationships governing transkingdom interactions in the intestine, including the dynamic coevolved relationship between the intestinal microbiota and innate and adaptive immunity. The field is now poised to define, in structural and biochemical terms, specific molecular mechanisms responsible for such transkingdom interactions. Future studies on the mammalian virome and transkingdom factors that influence viral infection may inspire new therapeutic approaches. In this Review, we explore the interplay between viruses, the microbiota, and host immune responses. We highlight how transkingdom interactions influence infection with mammalian enteric viruses, including pathogens.
Intestinal microbiota promote enteric virus replication.
Enteric viruses can interact with bacteria before initiating replication in the mammalian intestine. This illustration shows norovirus interacting with bacteria. Through these interactions, and/or through microbiota-mediated alteration of host immune responses, intestinal microbiota facilitate enteric virus replication in the gut.
Credit: K. Sutliff/
Science
Viruses that infect the intestine include major human pathogens (retroviruses, noroviruses, rotaviruses, astroviruses, picornaviruses, adenoviruses, herpesviruses) that constitute a serious public health problem worldwide. These viral pathogens are members of a large, complex viral community inhabiting the intestine termed “the enteric virome.” Enteric viruses have intimate functional and genetic relationships with both the host and other microbial constituents that inhabit the intestine, such as the bacterial microbiota, their associated phages, helminthes, and fungi, which together constitute the microbiome. Emerging data indicate that enteric viruses regulate, and are in turn regulated by, these other microbes through a series of processes termed “transkingdom interactions.” This represents a changing paradigm in intestinal immunity to viral infection. Here we review recent advances in the field and propose new ways in which to conceptualize this important area.
Antibody-dependent enhancement (ADE) of disease is a general concern for the development of vaccines and antibody therapies because the mechanisms that underlie antibody protection against any virus ...have a theoretical potential to amplify the infection or trigger harmful immunopathology. This possibility requires careful consideration at this critical point in the pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we review observations relevant to the risks of ADE of disease, and their potential implications for SARS-CoV-2 infection. At present, there are no known clinical findings, immunological assays or biomarkers that can differentiate any severe viral infection from immune-enhanced disease, whether by measuring antibodies, T cells or intrinsic host responses. In vitro systems and animal models do not predict the risk of ADE of disease, in part because protective and potentially detrimental antibody-mediated mechanisms are the same and designing animal models depends on understanding how antiviral host responses may become harmful in humans. The implications of our lack of knowledge are twofold. First, comprehensive studies are urgently needed to define clinical correlates of protective immunity against SARS-CoV-2. Second, because ADE of disease cannot be reliably predicted after either vaccination or treatment with antibodies-regardless of what virus is the causative agent-it will be essential to depend on careful analysis of safety in humans as immune interventions for COVID-19 move forward.
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