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Resurrection of endogenous retroviruses in antibody-deficient mice

Nature volume 491, pages 774–778 (2012)Cite this article

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Abstract

The mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These include the microbiota on environmental surfaces, such as the respiratory and gastrointestinal tracts1, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammalian genome2,3. The long-term consequences for the host of interactions with these microbial species can range from mutualism to parasitism and are not always completely understood. The potential effect of one microbial symbiont on another is even less clear. Here we study the control of ERVs in the commonly used C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic4 MLV in B6 mice with a range of distinct immune deficiencies affecting antibody production. These recombinant retroviruses establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV activation in immunodeficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer.

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Figure 1: eMLV activation in antibody-deficient mice.
Figure 2: Retroviraemia and leukaemias/lymphomas in antibody-deficient mice.
Figure 3: Mouse ERV activation by microbial products.
Figure 4: eMLV activation in antibody-deficiency depends on husbandry conditions.

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ArrayExpress

Data deposits

Primary microarray data from triplicate arrays were deposited at ArrayExpress under accession E-MEXP-3623.

Change history

  • 28 November 2012

    Affiliation 2 was corrected; formatting of the H2dlAb1-Ea allele in the main text was also corrected.

References

  1. Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Stocking, C. & Kozak, C. A. Murine endogenous retroviruses. Cell. Mol. Life Sci. 65, 3383–3398 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Stoye, J. P. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nature Rev. Microbiol. 10, 395–406 (2012)

    ADS  CAS  Google Scholar 

  4. Stoye, J. P. & Coffin, J. M. The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination. J. Virol. 61, 2659–2669 (1987)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. King, S. R., Berson, B. J. & Risser, R. Mechanism of interaction between endogenous ecotropic murine leukemia viruses in (BALB/c × C57BL/6) hybrid cells. Virology 162, 1–11 (1988)

    CAS  PubMed  Google Scholar 

  6. Demaria, O. et al. TLR8 deficiency leads to autoimmunity in mice. J. Clin. Invest. 120, 3651–3662 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. DeFranco, A. L., Rookhuizen, D. C. & Hou, B. Contribution of Toll-like receptor signaling to germinal center antibody responses. Immunol. Rev. 247, 64–72 (2012)

    PubMed  PubMed Central  Google Scholar 

  8. Browne, E. P. Regulation of B cell responses by Toll-like receptors. Immunology 136, 370–379 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kirkland, D. et al. B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage. Immunity 36, 228–238 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Li, M., Huang, X., Zhu, Z. & Gorelik, E. Sequence and insertion sites of murine melanoma-associated retrovirus. J. Virol. 73, 9178–9186 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pothlichet, J., Mangeney, M. & Heidmann, T. Mobility and integration sites of a murine C57BL/6 melanoma endogenous retrovirus involved in tumor progression in vivo. Int. J. Cancer 119, 1869–1877 (2006)

    CAS  PubMed  Google Scholar 

  12. Stoye, J. P., Moroni, C. & Coffin, J. M. Virological events leading to spontaneous AKR thymomas. J. Virol. 65, 1273–1285 (1991)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Young, G. R. et al. Negative selection by an endogenous retrovirus promotes a higher-avidity CD4+ T cell response to retroviral infection. PLoS Pathog. 8, e1002709 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Melamedoff, M., Lilly, F. & Duran-Reynals, M. L. Suppression of endogenous murine leukemia virus by maternal resistance factor. J. Exp. Med. 158, 506–514 (1983)

    CAS  PubMed  Google Scholar 

  15. Stoye, J. P. & Moroni, C. Endogenous retrovirus expression in stimulated murine lymphocytes. J. Exp. Med. 157, 1660–1674 (1983)

    CAS  PubMed  Google Scholar 

  16. Kozak, C. A. & Rowe, W. P. Genetic mapping of xenotropic murine leukemia virus-inducing loci in five mouse strains. J. Exp. Med. 152, 219–228 (1980)

    CAS  PubMed  Google Scholar 

  17. McCubrey, J. & Risser, R. Genetic interactions in induction of endogenous murine leukemia virus from low leukemic mice. Cell 28, 881–888 (1982)

    CAS  PubMed  Google Scholar 

  18. Moroni, C. & Schumann, G. Lipopolysaccharide induces C-type virus in short term cultures of BALB/c spleen cells. Nature 254, 60–61 (1975)

    ADS  CAS  PubMed  Google Scholar 

  19. Greenberger, J. S., Phillips, S. M., Stephenson, J. R. & Aaronson, S. A. Induction of mouse type-C RNA virus by lipopolysaccharide. J. Immunol. 115, 317–320 (1975)

    CAS  PubMed  Google Scholar 

  20. Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257–263 (2009)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lim, A. et al. Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection. AIDS 25, 1379–1383 (2011)

    CAS  PubMed  Google Scholar 

  22. Reid, R. R. et al. Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J. Immunol. 159, 970–975 (1997)

    CAS  PubMed  Google Scholar 

  23. Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nature Med. 17, 1585–1593 (2011)

    CAS  PubMed  Google Scholar 

  24. Wu, L. et al. Chronic acid water feeding protects mice against lethal gut-derived sepsis due to Pseudomonas aeruginosa. Curr. Issues Intest. Microbiol. 7, 19–28 (2006)

    CAS  PubMed  Google Scholar 

  25. Belancio, V. P., Roy-Engel, A. M. & Deininger, P. L. All y’all need to know ’bout retroelements in cancer. Semin. Cancer Biol. 20, 200–210 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Romanish, M. T., Cohen, C. J. & Mager, D. L. Potential mechanisms of endogenous retroviral-mediated genomic instability in human cancer. Semin. Cancer Biol. 20, 246–253 (2010)

    CAS  PubMed  Google Scholar 

  27. Lamprecht, B. et al. Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nature Med. 16, 571–579 (2010)

    CAS  PubMed  Google Scholar 

  28. Bannert, N. & Kurth, R. Retroelements and the human genome: new perspectives on an old relation. Proc. Natl Acad. Sci. USA 101, 14572–14579 (2004)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Trinchieri, G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu. Rev. Immunol. 30, 677–706 (2012)

    CAS  PubMed  Google Scholar 

  30. Park, M. A. et al. Common variable immunodeficiency: a new look at an old disease. Lancet 372, 489–502 (2008)

    PubMed  Google Scholar 

  31. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992)

    CAS  PubMed  Google Scholar 

  32. Philpott, K. L. et al. Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256, 1448–1452 (1992)

    ADS  CAS  PubMed  Google Scholar 

  33. Itohara, S. et al. T cell receptor δ gene mutant mice: independent generation of αβ T cells and programmed rearrangements of γδ TCR genes. Cell 72, 337–348 (1993)

    CAS  PubMed  Google Scholar 

  34. Cosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991)

    CAS  PubMed  Google Scholar 

  35. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. A. B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423–426 (1991)

    ADS  CAS  PubMed  Google Scholar 

  36. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988)

    ADS  CAS  PubMed  Google Scholar 

  37. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)

    CAS  PubMed  Google Scholar 

  38. Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002)

    ADS  CAS  PubMed  Google Scholar 

  39. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003)

    ADS  CAS  PubMed  Google Scholar 

  40. Young, G. R. et al. Negative selection by an endogenous retrovirus promotes a higher-avidity CD4+ T cell response to retroviral infection. PLoS Pathog. 8, e1002709 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hou, B., Reizis, B. & DeFranco, A. L. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29, 272–282 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)

    ADS  CAS  PubMed  Google Scholar 

  44. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002)

    CAS  Google Scholar 

  45. Chen, J. et al. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int. Immunol. 5, 647–656 (1993)

    CAS  PubMed  Google Scholar 

  46. Harriman, G. R. et al. Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes. J. Immunol. 162, 2521–2529 (1999)

    CAS  PubMed  Google Scholar 

  47. Uren, T. K. et al. Role of the polymeric Ig receptor in mucosal B cell homeostasis. J. Immunol. 170, 2531–2539 (2003)

    CAS  PubMed  Google Scholar 

  48. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000)

    CAS  PubMed  Google Scholar 

  49. Yoshinobu, K. et al. Selective up-regulation of intact, but not defective env RNAs of endogenous modified polytropic retrovirus by the Sgp3 locus of lupus-prone mice. J. Immunol. 182, 8094–8103 (2009)

    CAS  PubMed  Google Scholar 

  50. Karimi, M. M. et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell 8, 676–687 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Macfarlan, T. S. et al. Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes Dev. 25, 594–607 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jurka, J. et al. Repbase update, a database of eukaryotic repetitive elements. Cytogenet. Genome Res. 110, 462–467 (2005)

    CAS  PubMed  Google Scholar 

  53. Wang, J. et al. dbRIP: a highly integrated database of retrotransposon insertion polymorphisms in humans. Hum. Mutat. 27, 323–329 (2006)

    ADS  PubMed  PubMed Central  Google Scholar 

  54. Jern, P., Stoye, J. P. & Coffin, J. M. Role of APOBEC3 in genetic diversity among endogenous murine leukemia viruses. PLoS Genet. 3, e183 (2007)

    PubMed Central  Google Scholar 

  55. Bromham, L., Clark, F. & McKee, J. J. Discovery of a novel murine type C retrovirus by data mining. J. Virol. 75, 3053–3057 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lötscher, M. et al. Induced prion protein controls immune-activated retroviruses in the mouse spleen. PLoS ONE 2, e1158 (2007)

    ADS  PubMed  PubMed Central  Google Scholar 

  57. Katoh, K., Misawa, K., Kuma, K. & Miyata, T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 30, 3059–3066 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Martin, D. P. et al. RDP3: a flexible and fast computer program for analyzing recombination. Bioinformatics 26, 2462–2463 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Evans, L. H. et al. A neutralizable epitope common to the envelope glycoproteins of ecotropic, polytropic, xenotropic, and amphotropic murine leukemia viruses. J. Virol. 64, 6176–6183 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Bock, M., Bishop, K. N., Towers, G. & Stoye, J. P. Use of a transient assay for studying the genetic determinants of Fv1 restriction. J. Virol. 74, 7422–7430 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We wish to thank W.-D. Hardt for mouse samples and discussion, L. Sellés Vidal for technical assistance, and colleagues for critical reading of the manuscript. We also wish to thank the staff of the Unit for Laboratory Animal Medicine, University of Michigan, for the provision of germ-free mice. We are grateful for assistance from the Division of Biological Services, the Flow Cytometry, Electron Microscopy and Microarray facilities at NIMR. This work was supported by the UK Medical Research Council (U117581330 and U117512710).

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Authors and Affiliations

  1. Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK,

    George R. Young, Urszula Eksmond & George Kassiotis

  2. Basic Science Program, SAIC-Frederick, Inc. and Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute,

    Rosalba Salcedo

  3. National Institutes of Health, Frederick, 21701, Maryland, USA

    Rosalba Salcedo

  4. Centre d’Immunologie de Marseille-Luminy (CIML), Aix-Marseille University-UM2, INSERM-U1104, CNRS-UMR7280, Marseille, France,

    Lena Alexopoulou

  5. Division of Virology, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK,

    Jonathan P. Stoye

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Contributions

G.R.Y., J.P.S. and G.K. designed the study. G.R.Y. and U.E. carried out experiments and analysed data. R.S. and L.A. provided data or study samples. G.R.Y., J.P.S. and G.K. prepared the manuscript.

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Correspondence to George Kassiotis.

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Young, G., Eksmond, U., Salcedo, R. et al. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491, 774–778 (2012). https://doi.org/10.1038/nature11599

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