Investigating innate and adaptive immune responses against sexually transmitted viral infections

Abstract

Viral sexually transmitted pathogens, including herpes simplex viruses (HSV) and human immunodeficiency virus (HIV) are a major global health problem. In this study, genital mucosal immune response against viral sexually transmitted infections (STI), particularly in the early phase were investigated. Vaginal infection with HSV-2 in a mouse model results in epithelial layer breakdown and uncontrolled spread of the virus into the CNS. Therefore, it does not accurately reflect HSV-2 infection in humans. As such, a murine model of non-lethal STI using the flavivirus West Nile virus (WNV) has been developed, which is characterised by mild and self-limiting viral infection. Infection with both WNV and HSV-2 resulted in acute recruitment of macrophages, dendritic cells (DC), neutrophils and lymphocyte subsets from the bone marrow to the vagina and draining lymph nodes (ILN). Of interest, clusters of CD11c+ cells (but not CD11b or F4/80) were observed in close association with foci of epithelial cell infection. Although the infiltrating leukocytes in the vagina and ILN of C57BL/6 (Th1-prototype) and BALB/c (Th2-prototype) mice were comparable, the chemokines regulating DC and macrophage migration were differentially expressed in the two strains. In particular, CCL20 was only expressed in BALB/c mice, while CCL2 was expressed in the vagina of WNV-infected C57BL/6 mice. The reduction of several leukocyte subsets, including CCR2+ macrophages were observed after systemic CCL2 neutralisation, while, anti-CCL20 administration resulted in increased WNV infection in the vaginal epithelium. Moreover, macrophage migration was investigated using polystyrene beads. Interestingly, beads+ cells were found to accumulate in the spleen, suggesting several subsets of macrophages, DCs, neutrophils and lymphocytes become trapped and thus prevented from infiltrating the vagina and ILN. In addition, vaginal infection was associated with a dramatic upregulation of enzymatically active IDO. Thus, a possible antiviral or immunosuppressive role of IDO in this model was further investigated.