Chemokines and chemokine receptors that mediate immune defense to genital herpes simplex virus type 2 (HSV-2) infection

Herpes simplex virus type 2 (HSV-2) is a significant human pathogen that causes genital ulceration disease in humans. Chemokines play a significant role in the immune response to viral infection by influencing the recruitment of effector cells (NK and T cells) to sites of infection. CXCL9 & CXCL10 signal through the sole receptor CXCR3, preferentially expressed on activated NK and T cells. Likewise, CCR5 expression on these effector cells has also been associated with their recruitment during viral infection. The relevance of CXCR3 ligands (CXCL9 & CXCL10) as well as CXCR3 and CCR5 expression relative to the host immune response to acute genital HSV-2 infection has remained unclear. Here, we demonstrate the requirement of CCR5 for NK cell migration, CXCL9 & CXCL10 for NK and virus-specific T cell migration, and CXCR3 for cytolytic function of HSV-2-specific CD8 + T cells following acute genital HSV-2 infection. Mice deficient in CCR5 (CCR5-/-), CXCL9 (CXCL9-/-), CXCL10 (CXCL10-/-), and CXCR3 (CXCR3-/-) responded poorly to viral infection compared to WT animals in terms of HSV-2 titer and mortality. In CCR5-/- mice, a deficiency in NK cell recruitment to the CNS was detected following infection. On the other hand, CXCR3 -/- mice showed no defect in the recruitment of NK cells to sites of infection. However, a defect in cytolytic activity by HSV-2-specific CD8 + T cells was found. Associated with diminished cytolytic activity, impaired T cell capping and a decrease in T-bet, perforin and granzyme B expression were observed. In conclusion, CXCR3- and CCR5-expressing effector T and NK cells act in concert to maximize resistance to genital HSV-2 in terms of local viral replication in the vaginal tract and spread to the CNS. The temporal and tissue-specific nature of CXCR3 ligand (CXCL9 & CXCL10) expression within the inflamed tissue is a necessary contributing factor to optimize the host immune response both in the vaginal tissue and CNS. These results have an application to fundamental problems inherent within genital herpes infection.