Herpes simplex virus (HSV) is a DNA containing, enveloped virus that is a natural pathogen of humans. In immunocompetent individuals, HSV infections of the orofacial or genitourinary mucosal epithelia are generally limited, presenting as either a subclinical infection, or as a highly defined vesicular lesion which heals rapidly. The hallmark of HSV infections, however, is their ability to enter the sensory neurons of the peripheral nervous system (PNS) and establish a latent infection. In approximately 30% of infected immunocompetent individuals, HSV reactivates from the latent state, migrate back down the axonal processes and reinitiate a recrudescent infection at the original site of infection. The reasons for the variability of recrudescent infection within the population is not known, but may reflect the efficiency of the host immune mechanisms in controlling the initial phase of infection. HSV infections may be devastating in individuals whose immune responses are impaired due to immunosuppressive infections or neoplasias or immunosuppressive chemotherapeutic treatment. In these individuals, HSV may disseminate, involve the central nervous system (CNS), and possibly cause death. This increased susceptibility is likely to reflect dysfunction within the T lymphocyte compartment of the immune system. However, T cell impairment does not always result in severe, disseminated HSV infection in infected, immunosuppressed individuals. A critical factor may be the ability of the host to successfully control initial infection. The successful limitation of infection may be sufficient to prevent subsequent episodes of recrudescent infection, even under conditions of severe immunological impairment. In this proposal, a well defined murine model of cutaneous HSV infection will be used in which control of infection is highly efficient and dependent upon intact T cell function. The dissection of the T cell subset(s) responsible and the mechanisms by which HSV is limited may give insight into the """"""""optimal"""""""" response to this pathogen. The principal focus will be upon the role of the CD8 T cell subset and the cytokine interferon-gamma (IFN-gamma) in controlling primary HSV infection within skin and the PNS.
In Aim 1, the characteristics of HSV multiplication and spread within these two sites of infection will be determined in CD8 T cell-deficient mice. The levels of infectious HSV attained within the skin of the footpad and within individual spinal ganglia segments will be assessed. The relationship between the expression of immune functions within infected tissues and the draining regional lymph node and the limitation of HSV in skin and PNS will be assessed.
In Aim 2, the function and specificity of CD8 T cells which mediate viral clearance in skin and PNS will be investigated using an adoptive transfer model. Specifically, the relative contribution of IFN-gamma within the skin and PNS will be assessed by treating recipient mice with neutralizing anti-IFN-gamma antibody.
In Aim 3, the importance of IFN-gamma will be more investigated in more detail using models in which the cytokine is absent or neutralized throughout the course of infection and by the infusion of recombinant murine IFN-gamma (r-mu-IFN-gamma) in vivo. Potential mechanisms by which IFN-gamma may mediate its effect will be investigated.
