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Resurrection of endogenous retroviruses in antibody-deficient mice

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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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Primary accessions

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.

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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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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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The authors declare no competing financial interests.

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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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