IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

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-36γ in the context of HSV-2 Infection. In 3-D VEC, IL-36γ is induced by HSV-2 Infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital Infection model. We showed that IL-36γ 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-36γ 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-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ 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-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

3-D bioreactor model; Antimicrobial peptides; Chemokines; HSV-2 mouse model; Host defense; IL-36 family members; Polymorphonuclear leukocytes; Sexually transmitted infections; Vaginal epithelial cells.