Herpes simplex virus and the chemokines that mediate the inflammation

Abstract

Herpes simplex viruses (HSV) are highly pervasive pathogens in the human host with a seroconversion rate upwards of 60% worldwide. HSV type 1 (HSV-1) is associated with the disease herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world. Individuals suffering from genital herpes associated with HSV type 2 (HSV-2) are found to be two- to threefold more susceptible in acquiring human immunodeficiency virus (HIV). The morbidity associated with these infections is principally due to the inflammatory response, the development of lesions, and scarring. Chemokines have become an important aspect in understanding the host immune response to microbial pathogens due in part to the timing of expression. In this paper, we will explore the current understanding of chemokine production as it relates to the orchestration of the immune response to HSV infection.

Figure 1

Expression of inflammatory cytokines and chemokines in the cornea of HSV-1 infected mice. C57BL/6 female mice (n=6/timepoint) were left alone (basal) or scarified (0) and infected with HSV-1 (McKrae strain, 1000 plaque forming units (PFU)/eye. Twenty-four to thirty-six hours postinfection, the mice were euthanized, perfused, and the cornea was removed and homogenized in a buffer containing a cocktail of protease inhibitors. The supernatant was clarified (10,000 × g, 5 min) and assayed for cytokine/chemokine content by ELISA. Bars represents mean ± SEM for each analyte under measure.

Figure 2

Chemokine expression in the cornea following HSV-1 infection. Three different scenarios can operate in the production of chemokines within the cornea following ocular HSV-1 infection. In 1a, HSV-1 DNA CpG motifs bind to the intracellular toll-like receptor (TLR)9 eliciting the production of CXCL10 through NFκB activation. In 1b, HSV-1 enters the epithelial cell and following transcription induces the production of IFN-α which induces CXCL10 production. In 2, HSV-1 activation of NFκB stimulates IL-1α synthesis leading to IL-6 production resulting in CXCL2 and CCL3 expression. These chemokines draw in PMNs and T cells. PMNs can secrete CXCL9 and CXCL10 which can recruit additional leukocytes including macrophages, dendritic cells, NK cells, and T cells.