title: Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa.
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.
authors.affiliation: Laboratory of Host Defenses, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea;
authors.forename: Byoung-Chan
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Korean Collection for Type Cultures, Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea;
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Chang
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea;
authors.forename: Meehyang
authors.initials: M
authors.lastname: Kwon
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea;
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea;
authors.forename: Dukjin
authors.initials: D
authors.lastname: Kang
authors.affiliation: Division of Mass Spectrometry Research, Korea Basic Science Institute, Ochang 28119, Republic of Korea;
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
authors.forename: Inhwa
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: 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.
authors.forename: Heung Kyu
authors.identifier: http://orcid.org/0000-0002-3977-1510
authors.initials: HK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000276:immunology*; D015169:Colony Count, Microbial; D064806:Dysbiosis / Q000150:complications*; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000473:pathology / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D000067596:Interleukin-33 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology* / Q000821:virology; D010447:Peptide Hydrolases / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D000067596:Interleukin-33; D007371:Interferon-gamma; D010447:Peptide Hydrolases
keywords: IL-33; commensal microbiota; dysbiosis; genital tract; herpes simplex virus type 2
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