Immunoregulatory Functions of Interferons During Genital HSV-2 Infection

Abstract

Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections that disproportionately impacts women worldwide. Currently, there are no vaccines or curative treatments, resulting in life-long infection. The mucosal environment of the female reproductive tract (FRT) is home to a complex array of local immune defenses that must be carefully coordinated to protect against genital HSV-2 infection, while preventing excessive inflammation to prevent disease symptoms. Crucial to the defense against HSV-2 infection in the FRT are three classes of highly related and integrated cytokines, type I, II, and III interferons (IFN). These three classes of cytokines control HSV-2 infection and reduce tissue damage through a combination of directly inhibiting viral replication, as well as regulating the function of resident immune cells. In this review, we will examine how interferons are induced and their critical role in how they shape the local immune response to HSV-2 infection in the FRT.

Keywords: HSV – 2; female reproductive tract (FRT); genital mucosa; immune regulation; type I interferon (IFN); type II interferon; type III interferons.

Figure 1

IFNs regulating innate and adaptive immunity to genital HSV-2 infection. Type I and III IFNs directly suppress HSV-2 replication in the genital mucosa. Concurrently, type I IFN signaling promotes IM recruitment and production of IL-18. This in turns stimulates NK cell IFN-γ production. Type I IFNs stimulate adaptive immunity both directly and indirectly through IM differentiation into APCs, maturation of DCs, and inducing CD4+ T cell expansion. Type I IFNs can both promote neutrophil function, and negatively regulate innate immune responses to prevent immune-mediated pathology by suppressing neutrophil recruitment and limiting IFN-γ production by NK cells. IFN-γ production, highly dependent on type I IFN signaling, promotes IgG2 antibody production, M1 macrophage polarisation and DC maturation, which will promote CD4+ memory T cell retention via production of CCL4 and CXCL9. Type III IFNs, similar to type I IFNs, have also been shown to suppress neutrophil activity and monocyte-mediated NK cell activation, but this is not yet demonstrated in the vaginal mucosa.