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B cells are the predominant mediators of early systemic viral dissemination during rectal LCMV infection

Mucosal Immunologyvolume 11pages11581167 (2018) | Download Citation

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Abstract

Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T-cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node. Here, we show that rectal infection with LCMV triggers type I/III interferon responses, followed by innate immune activation and lymphocyte recruitment to the colon. In contrast to vaginal exposure, innate immunity controls LCMV replication in the colon, but virus rapidly disseminates systemically. Virus-induced inflammation promotes the recruitment of LCMV target cells to the colon followed by splenic viral dissemination by infected B cells, and to a lesser extent by CD8 T cells. These findings demonstrate major immunological differences between vaginal and rectal exposure to the same viral pathogen, highlighting unique risks associated with each of these common routes of sexual viral transmission.

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Acknowledgements

We thank J. C. de la Torre (Scripps) for LCMV-GFP; C. Allen (UCSF) for muMT mice; E. Woodruff, J. Luong, and I. Lew for maintaining animal colonies and technical assistance. We are grateful to W. C. Greene (Gladstone), J. G. Cyster (UCSF), N. R. Roan (UCSF), M. Ott (Gladstone), and K. Fontaine (Gladstone) for critical reading of the manuscript, and to G. Howard (Gladstone) for editorial assistance. This publication was made possible with help from the University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR), an NIH-funded program (P30 AI027763), NIH S10 RR028962, and the James B. Pendelton Charitable Trust, all supporting the Gladstone Flow Core and cell sorter. The Gladstone Institutes received support for its animal care facility from a National Center for Research Resources grant (RR18928). This work was supported by grants from the National Institutes of Health (DP2 AI112244), a University of California Hellman Award, a Center for AIDS Research (CFAR) Pilot Award (P30 AI027763), and CNIHR (P30 AI027767) to S.S.

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Affiliations

  1. Virology and Immunology, Gladstone Institutes, San Francisco, CA, 94158, USA

    • Martin Trapecar
    • , Shahzada Khan
    • , Benjamin L. Cohn
    • , Frank Wu
    •  & Shomyseh Sanjabi
  2. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, 94143, USA

    • Shomyseh Sanjabi

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Contributions

Conceptualization: S.S. and M.T.; Methodology: M.T., B.L.C., S.K., and S.S.; Formal analysis: M.T.; Investigation: M.T., S.K., B.L.C., F.W.; Resources: S.S.; Writing (original draft): S.S. and M.T.; Writing (review and editing): S.S., M.T., S.K.; Visualization: M.T. and S.S; Supervision: S.S. and M.T.; and Funding acquisition: S.S.

Conflict of interest

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shomyseh Sanjabi.

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DOI

https://doi.org/10.1038/s41385-018-0009-4