Letter | Published:

An enteric virus can replace the beneficial function of commensal bacteria

Nature volume 516, pages 9498 (04 December 2014) | Download Citation

Abstract

Intestinal microbial communities have profound effects on host physiology1. Whereas the symbiotic contribution of commensal bacteria is well established, the role of eukaryotic viruses that are present in the gastrointestinal tract under homeostatic conditions is undefined2,3. Here we demonstrate that a common enteric RNA virus can replace the beneficial function of commensal bacteria in the intestine. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice restored intestinal morphology and lymphocyte function without inducing overt inflammation and disease. The presence of MNV also suppressed an expansion of group 2 innate lymphoid cells observed in the absence of bacteria, and induced transcriptional changes in the intestine associated with immune development and type I interferon (IFN) signalling. Consistent with this observation, the IFN-α receptor was essential for the ability of MNV to compensate for bacterial depletion. Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection. These data indicate that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similarly to commensal bacteria.

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Accessions

Primary accessions

Gene Expression Omnibus

Referenced accessions

NCBI Reference Sequence

Data deposits

RNA-seq data have been deposited in the Gene Expression Omnibus under accession number GSE60163. The MNV.SKI capsid sequence has been deposited in the NCBI Reference Sequence database under accession number KM463105.

References

  1. 1.

    & The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012)

  2. 2.

    & Resident viruses and their interactions with the immune system. Nature Immunol. 14, 654–659 (2013)

  3. 3.

    The virome in mammalian physiology and disease. Cell 157, 142–150 (2014)

  4. 4.

    , & Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 146, 1459–1469 (2014)

  5. 5.

    , , & Norovirus pathogenesis: mechanisms of persistence and immune evasion in human populations. Immunol. Rev. 225, 190–211 (2008)

  6. 6.

    , , & Describing the silent human virome with an emphasis on giant viruses. Intervirology 56, 395–412 (2013)

  7. 7.

    , , , & Development of PCR assays with nested primers specific for differential detection of three human anelloviruses and early acquisition of dual or triple infection during infancy. J. Clin. Microbiol. 46, 507–514 (2008)

  8. 8.

    et al. Use of a TT virus ORF1 recombinant protein to detect anti-TT virus antibodies in human sera. J. Gen. Virol. 81, 2949–2958 (2000)

  9. 9.

    et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011)

  10. 10.

    , , & Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499, 219–222 (2013)

  11. 11.

    et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338 (2010)

  12. 12.

    et al. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell 151, 253–266 (2012)

  13. 13.

    , , , & IV STAT1-dependent innate immunity to a Norwalk-like virus. Science 299, 1575–1578 (2003)

  14. 14.

    et al. Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2, e432 (2004)

  15. 15.

    et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010)

  16. 16.

    & The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009)

  17. 17.

    et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011)

  18. 18.

    et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011)

  19. 19.

    et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012)

  20. 20.

    et al. Murine noroviruses comprising a single genogroup exhibit biological diversity despite limited sequence divergence. J. Virol. 81, 10460–10473 (2007)

  21. 21.

    et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014)

  22. 22.

    et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. Infect. Immun. 79, 1536–1545 (2011)

  23. 23.

    et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012)

  24. 24.

    et al. Outbreak of human calicivirus gastroenteritis in a day-care center in Sydney, Australia. J. Clin. Microbiol. 29, 544–550 (1991)

  25. 25.

    , , , & Asymptomatic human calicivirus infection in a day care center. Pediatr. Infect. Dis. J. 9, 190–195 (1990)

  26. 26.

    , , & Immunomodulatory functions of type I interferons. Nature Rev. Immunol. 12, 125–135 (2012)

  27. 27.

    et al. Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm. Bowel Dis. 20, 431–443 (2014)

  28. 28.

    & Viral surveillance and discovery. Curr Opin Virol 3, 199–204 (2013)

  29. 29.

    et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14, 216–224 (2013)

  30. 30.

    , , & Protruding domain of capsid protein is necessary and sufficient to determine murine norovirus replication and pathogenesis in vivo. J. Virol. 86, 2950–2958 (2012)

  31. 31.

    , & Plaque assay for murine norovirus. J. Vis. Exp. e4297 (2012)

  32. 32.

    et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008)

  33. 33.

    , & edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010)

  34. 34.

    , & Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

  35. 35.

    , , & Pitfalls in mouse norovirus (MNV) detection in fecal samples using RT-PCR, and construction of new MNV-specific primers. Exp. Anim. 62, 127–135 (2013)

  36. 36.

    , , & Molecular characterization of murine norovirus isolates from South Korea. Virus Res. 147, 1–6 (2010)

  37. 37.

    et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008)

  38. 38.

    et al. Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses. J. Virol. 81, 3251–3263 (2007)

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Acknowledgements

We would like to thank S. Koralov and P. Loke for advice on the manuscript, E. Venturini for assistance with deep sequencing, S. Brown and Z. Tang for data analysis, L. Ciriboga for CD3 staining, the flow cytometry and histopathology cores (Cancer Center Support Grant, P30CA016087) for assistance with sample preparation and analyses, M. Alva and D. Littman for assistance with breeding and maintaining GF mice, and H. Moura Silva for sample collection for MNV isolation. This research was supported by National Institutes of Health grant R01 DK093668 (K.C.) and a New York University Whitehead Fellowship (K.C.), Vilcek Fellowship (E.K.) and Erwin Schrödinger Fellowship from the Austrian Science Foundation (E.K.).

Author information

Affiliations

  1. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA

    • Elisabeth Kernbauer
    •  & Ken Cadwell
  2. Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA

    • Elisabeth Kernbauer
    •  & Ken Cadwell
  3. New York Presbyterian Hospital, New York, New York 10065, USA

    • Yi Ding
  4. Department of Pathology, New York University School of Medicine, New York, New York 10016, USA

    • Yi Ding

Authors

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Contributions

E.K. performed all the experiments, Y.D. analysed and scored histological sections, K.C. and E.K. designed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ken Cadwell.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Information

    This file contains the RNAseq table. Sheet 1 and sheet 2 show the mRNA counts for GF (uni N = 3), GF+MNV (MNV, N = 4) and GF+conv (conv, N = 4) which are above the threshold cutoff and which have been ranked according to their p-value after edgeR analysis. In sheet 1, ranked genes in the comparison GF to GF+MNV are shown; in sheet 2, GF was compared to GF+conv. For each gene the log fold change (logFC), log counts per million (log CPM) as well as the false discovery rate (FDR, calculated with the Benjamini’s and Hochberg algorithm) are shown.

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DOI

https://doi.org/10.1038/nature13960

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