Murine norovirus infection does not cause major disruptions in the murine intestinal microbiota

Nelson, Adam M.; Elftman, Michael D.; Pinto, Amelia K.; Baldridge, Megan T.; Hooper, Patrick; Kuczynski, Justin; Petrosino, Joseph F.; Young, Vincent B.; Wobus, Christiane E.

doi:10.1186/2049-2618-1-7

Cited by 37 publications

(31 citation statements)

References 33 publications

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“…Consistent with a previous report 52 , CR6 infection had no effect on luminal or colon-associated microbial communities in STAT1-sufficient animals. However, maintenance of colonic-tissue associated community structure was STAT1-dependent, which we considered indicative of potential bacterial translocation that could contribute to CR6-induced pathology.…”

Section: Discussionsupporting

confidence: 92%

STAT1-dependent tolerance of intestinal viral infection

et al. 2020

Preprint

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1Recent evidence indicates that viral components of the microbiota can contribute to intestinal 2 homeostasis and protection from local inflammatory or infectious insults. However, host-derived 3 mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use 4 colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-5 directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of 6 tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, 7 prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4 + and 8 CD8 + T cell responses. In contrast to systemic viral pathogens that drive T cell mediated 9 immunopathology in STAT1-deficient mice, our data indicates that loss of CD4 + or CD8 + T cells 10 and their associated effector functions has no effect on CR6-induced disease. However, 11 therapeutic administration of an antiviral compound to limit viral replication prevented viral-12 induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. 13Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell 14 responses from innate immune-mediated restriction of viral replication that is necessary for 15 intestinal viral tolerance. 16 17 34 antiviral treatment can enhance DSS-induced colonic inflammation in mice 8 , indicating that even 35 in the presence of a complex microbiota, the virome (composed of bacteriophage, endogenous 36 retroviruses, and eukaryotic viruses) contributes to intestinal homeostasis. Supporting the 37 hypothesis that host-encoded mechanisms regulate and tolerate viral colonization, latent or 38 chronic viral infection can be reactivated by helminth infection in a STAT6 and interferon (IFN)g-39 dependent manner 9 . 40 41 3 MNV CR6 (CR6) demonstrates features of a mutualistic host-microbe interaction and is an 42 attractive model to interrogate commensal tolerance to a eukaryotic virus. In addition to 43 providing supportive signals in immunosufficient GF mice 7,10 , this strain can establish persistent 44 colonic infection with continued shedding for at least two months in the absence of any 45 detectable clinical or histopathological signs in wildtype (WT) mice 11 . Once MNV was 46 identified 12 , sentinel screening of animal units across North America and Europe identified its 47 57 an IL-22/STAT1-dependent mechanism limits intestinal epithelial cell (IEC)-intrinsic viral 58 replication and RV-induced intestinal pathology 22 . Following vaccinia virus infection, STAT1 59 supports optimal antiviral CD8 + T cell expansion and survival 23,24 . In contrast, STAT1-deficient 60 mice exhibit increased numbers of both CD4 + and CD8 + T cells in response to infection with 61 LCMV Armstrong, although these cells do not constrain viral replication 25 . Instead, Stat1 -/mice 62 succumb rapidly to CD4 + T cell mediated immunopathology 25 . Indeed, tissue damage caused by 63 dysregulated lymphocyte su...

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Section: Discussionsupporting

confidence: 92%

STAT1-dependent tolerance of intestinal viral infection

et al. 2020

Preprint

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“…A subset (20%) of HNoV-infected individuals exhibited enhanced F/B ratios [87], while MNV-1 enhanced F/B ratios in C57BL/6 mice at Day 5 postinfection [88]. However, longitudinal analyses of both C57BL/6 (MNV-1, MNV.CR6) and Swiss Webster (MNV-1, MNV-4) mice failed to detect MNoV-induced dysbiosis of gastrointestinal bacteria at the phylum level [89]. A reduction in intestinal Lactobacillus strains occurred in MNV1-infected ICR mice, with a concurrent increase in Proteobacteria delta , mirroring findings from HNoV [89].…”

Section: Interactions Of Nov With the Microbiotamentioning

confidence: 99%

“…However, longitudinal analyses of both C57BL/6 (MNV-1, MNV.CR6) and Swiss Webster (MNV-1, MNV-4) mice failed to detect MNoV-induced dysbiosis of gastrointestinal bacteria at the phylum level [89]. A reduction in intestinal Lactobacillus strains occurred in MNV1-infected ICR mice, with a concurrent increase in Proteobacteria delta , mirroring findings from HNoV [89]. On the flip side, experimentally induced bacterial dysbiosis also alters MNoV infection.…”

Section: Interactions Of Nov With the Microbiotamentioning

confidence: 99%

Norovirus Regulation by Host and Microbe

Baldridge

Turula

Wobus

2016

Trends in Molecular Medicine

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Norovirus (NoV) infection is the leading cause of epidemic gastroenteritis globally, and can lead to detrimental chronic infection in immunocompromised hosts. Despite its prevalence as a cause of diarrheal illness, the study of human NoVs (HNoVs) has historically been limited by a paucity of models. The use of murine NoV (MNoV) to interrogate mechanisms of host control of viral infection has facilitated the exploration of different genetic mouse models, revealing roles for both innate and adaptive immunity in viral regulation. MNoV studies have also recently identified important interactions between the commensal micro-biota and NoV with clear extensions to HNoVs. In this review, we discuss the most current understanding of how the host, the microbiome, and their interactions regulate NoV infections.

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“…Conflicting reports exist whether MuNoV infection alters the composition of the microbiota in immunocompetent mice. No major changes were observed in the intestinal microbiota of inbred C57BL/6 or outbred Swiss Webster mice infected with MNV-1, MNV-4, or CR6 (145). In another study, a significant reduction in the Bacteroidetes/Firmicutes ratio was observed in MNV-1-infected C57BL/6 mice compared to mock-inoculated controls (101).…”

Section: Influence Of Murine Norovirus On Biomedical Research Modelsmentioning

confidence: 98%

Viruses in Rodent Colonies: Lessons Learned from Murine Noroviruses

Karst

Wobus

2015

Annu. Rev. Virol.

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Noroviruses (NoVs) are highly prevalent, positive-sense RNA viruses that infect a range of mammals, including humans and mice. Murine noroviruses (MuNoVs) are the most prevalent pathogens in biomedical research colonies, and they have been used extensively as a model system for human noroviruses (HuNoVs). Despite recent successes in culturing HuNoV in the laboratory and a small animal host, studies of human viruses have inherent limitations. Thus, the versatility of the MuNoV system with its native host, reverse genetics and cell culture systems will continue to provide important insights into NoV and enteric virus biology. In the current review, we will summarize recent findings from MuNoV that increase our understanding of enteric virus pathogenesis and highlight similarities between human and murine NoVs that underscore the value of MuNoV to inform studies of HuNoV biology. We also discuss the potential of endemic MuNoV infections to impact other disease models.

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Murine norovirus infection does not cause major disruptions in the murine intestinal microbiota

Cited by 37 publications

References 33 publications

STAT1-dependent tolerance of intestinal viral infection

STAT1-dependent tolerance of intestinal viral infection

Norovirus Regulation by Host and Microbe

Viruses in Rodent Colonies: Lessons Learned from Murine Noroviruses

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