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Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):E762-71. doi: 10.1073/pnas.1518589113. Epub 2016 Jan 25.

Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa.

Author information

1
Laboratory of Host Defenses, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
2
Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea;
3
Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea;
4
Division of Mass Spectrometry Research, Korea Basic Science Institute, Ochang 28119, Republic of Korea;
5
Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
6
Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
7
Laboratory of Host Defenses, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; heungkyu.lee@kaist.ac.kr.

Abstract

Commensal microbiota are well known to play an important role in antiviral immunity by providing immune inductive signals; however, the consequence of dysbiosis on antiviral immunity remains unclear. We demonstrate that dysbiosis caused by oral antibiotic treatment directly impairs antiviral immunity following viral infection of the vaginal mucosa. Antibiotic-treated mice succumbed to mucosal herpes simplex virus type 2 infection more rapidly than water-fed mice, and also showed delayed viral clearance at the site of infection. However, innate immune responses, including type I IFN and proinflammatory cytokine production at infection sites, as well as induction of virus-specific CD4 and CD8 T-cell responses in draining lymph nodes, were not impaired in antibiotic-treated mice. By screening the factors controlling antiviral immunity, we found that IL-33, an alarmin released in response to tissue damage, was secreted from vaginal epithelium after the depletion of commensal microbiota. This cytokine suppresses local antiviral immunity by blocking the migration of effector T cells to the vaginal tissue, thereby inhibiting the production of IFN-γ, a critical cytokine for antiviral defense, at local infection sites. These findings provide insight into the mechanisms of homeostasis maintained by commensal bacteria, and reveal a deleterious consequence of dysbiosis in antiviral immune defense.

KEYWORDS:

IL-33; commensal microbiota; dysbiosis; genital tract; herpes simplex virus type 2

PMID:
26811463
PMCID:
PMC4760794
DOI:
10.1073/pnas.1518589113
[Indexed for MEDLINE]
Free PMC Article

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