This K01 application proposes a 5-year program to: (1) provide the structure and funding for a comprehensive educational and research experience for the candidate's development as an independent academic research scientist, and 2) apply new expertise in neuroimmunology and neurovirology to strengthen and expand research initiatives in the Department of Neuroscience at the University of Pittsburgh. The candidate's long-term research and career goals are to develop an independent research program examining the neurobiological basis for how stress alters anti-viral immunity, and to identify strategies that reduce the effects of stress on the incidence and severity of alpha herpes viral infections in the CNS. With the guidance of the principal preceptor, Dr. Alan Sved, and other mentors, Drs. J. Patrick Card, Gloria Hoffman, and Bruce Rabin, the candidate aims to acquire the skills necessary to study neuro-immune interactions, and viral infections in the CNS. The hypotheses proposed are derived from a theoretical framework that contends that psychogenic or somatic stress effects specific neural elements within the brain's arousal systems which modify neurohormonal influences on immune function.
The specific aims are to examine how: (1) stress alters the extent of viral infectivity in the CNS; (2) stress alters anti-viral responses to a neurotropic viral infection in the CNS; and (3) pharmacological treatments that block the effects of stress on CNS function, ameliorate the effects of stress on anti-viral immunity. The effects of restraint stress on the passage of a swine alpha-herpes virus (pseudorabies, PRV) through synaptically-linked neural circuits will be examined after intravitreal injection of this virus in rats. This in vivo CNS neurotropic viral infection model will be used because the pattern of anterograde passage and the temporal aspects of transneuronal transport of intravitreal administered PRV from the ganglion cells in the retina to vision-related projection sites in the brain are well-characterized. The effects of stress on the responses of glial cells and mononuclear leukocytes to the viral infection will be examined in relation to the passage and cytopathogenicity of PRV in the CNS using light microscopy immunohistochemical techniques. Results from the proposed studied may: (1) provide evidence that definitively establishes that the neurobiological responses to stress are the determinants for stress-induced alterations in anti-viral immunity, and (2) have important implications for the use of pharmaceutical treatments to reduce the effects of stress on the incidence and severity of CNS viral infections.
