IL-36? induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis.
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ABSTRACT: Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36? in the context of HSV-2 infection. In 3-D VEC, IL-36? is induced by HSV-2 infection, and pretreatment with exogenous IL-36? significantly reduced HSV-2 replication. To assess the impact of IL-36? treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36? treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36? treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36? treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36? drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36? may participate as a key player in host defense mechanisms against invading pathogens in the FRT.
SUBMITTER: Gardner JK
PROVIDER: S-EPMC6291016 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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