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IL‐36&ggr; induces a transient HSV‐2 resistant environment that protects against genital disease and pathogenesis

Jameson K. Gardner,Melissa M. Herbst‐Kralovetz

Published 2018 in Cytokine

ABSTRACT

HighlightsHSV‐2 infection induces IL‐36&ggr; expression in human vaginal epithelial cells.HSV‐2 replication is limited by IL‐36&ggr; treatment in vitro and in vivo.IL‐36&ggr; induces immune mediators and PMN recruitment in the vaginal epithelium.Treatment with IL‐36&ggr; protects against genital HSV‐2 disease and pathogenesis.IL‐36&ggr; may function as a key defense mechanism in the female reproductive tract. 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&ggr; in the context of HSV‐2 infection. In 3‐D VEC, IL‐36&ggr; is induced by HSV‐2 infection, and pretreatment with exogenous IL‐36&ggr; significantly reduced HSV‐2 replication. To assess the impact of IL‐36&ggr; treatment on HSV‐2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL‐36&ggr; 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&ggr; 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&ggr; treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL‐36&ggr; 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&ggr; may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

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