11: Modulation of immunity against genital Herpes simplex virus

Viral sexually transmitted infections (STI) are a significant health problem worldwide. Recently, there has been enhanced focus on Herpes simplex virus type 2 (HSV-2), as a STI model to understand anti-viral immune responses at mucosal surfaces. Here we report that HSV-2 infection is accompanied by massive induction of IFN- γ in two waves, at day 2 and 5 post infection (p.i.), which in turn, induces indoleamine 2,3 deoxygenase (IDO) in infected vaginal epithelial cells, initiating the degradation of L-tryptophan (L-Trp), along the kynurenine pathway. Kynurenine is undetectable at day 0 p.i., but increases over the 7 day infection course, while, L-Trp concentrations decrease correspondingly to about 1.5 μM. Since the concentration of L-Trp increases over this time in the vaginal draining lymph node (DLN), it seems likely that IDO acts at the site of infection to inhibit virus replication, rather than suppressing the adaptive immune response. Indeed, HSV-2 RNA copies in the vagina were significantly higher in IDO knockout (KO) mice, emphasizing this point. Interestingly, IL-10, expressed by some monocyte-derived cells, was higher in IDO KO mice, showing similar kinetics to IFN- γ and IDO expression in wild type mice. Monocyte-derived macrophages and dendritic cells coming from the bone marrow, as shown by adoptive transfer studies, infiltrated beneath areas of epithelial infection, peaking at day 5 p.i., in similar numbers in both strains, corresponding with the peak of epithelial CCL2 expression. Indeed, CCL2 Ab blockade significantly reduced numbers of these cells. We are investigating whether these infiltrating myeloid cells are the source of IL-10, but our findings suggest that antiviral IDO normally controls immunosuppressive IL-10 signals that might otherwise lead to higher viral loads.