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 virusspecific 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.commensal microbiota | dysbiosis | IL-33 | herpes simplex virus type 2 | genital tract

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…Following vaginal infection, CD4 + T cell-derived IFN-γ activates FRT epithelium to produce CXCL9/10 and enhance the migration of antigen-specific effector CD8 + T cells in a CXCR3-dependent fashion. 98 Dysbiosis-induced IL-33 production leads to greatly enhanced ILC2 (type 2 innate lymphoid cell) mediated accumulation of eosinophils and defective recruitment of both CD4 + and CD8 + T cells after vaginal herpes virus infection, 99 suggesting a potential crosstalk between lower FRT associated microbiome and T RM formation. Different from current paradigm that DCs carry local antigens to the draining LNs to prime antigen-specific naïve T cells, lower FRT mucosa is able to support naïve CD8 + T cell priming and proliferation in situ without the involvement of secondary lymphoid organs.…”

IL-33 and the intestine: The good, the bad, and the inflammatory

“…Immunity at mucosal surfaces is notable for the presence of commensal bacteria [80]. In the gut, the microbiome has been established to be a significant mediator of metabolism and local inflammation [81–85].…”

Challenges in conducting research on sexual violence and HIV and approaches to overcome them

“…For all community participants, we tried to ensure that the samples were free of blood, semen and vaginal lubricant, as these can obscure the biomarkers being studied. In addition to all of the above, we had to reschedule if a participant was on antibiotics as the presence of certain medications can impact the genital immune microenvironment 40 .…”

“…In addition to all of the above, we had to reschedule if a participant was on antibiotics as the presence of certain medications can impact the genital immune microenvironment. 40 Assuring the concordance of all these factors while sampling as soon as possible after sexual assault proved to be a formidable challenge, but the use of a shared online calendar as well as regular communication between members of the study team facilitated the process. Among community-recruited participants, the samples were occasionally contaminated or a visit had to be rescheduled due to unexpected menstrual bleeding or recent sexual activity.…”