Cytomegalovirus (CMV) is an important opportunistic pathogen with an estimated prevalence in the human population of 50-90%. While most immunocompetent individuals do not develop clinical infection, immunosuppressed patients such as those with AIDS or undergoing immunosuppressive therapy open develop debilitating neurological deficits, mental disorders, cognitive impairment, and potentially fatal infection. CMV also may further suppress the immune system and has been suggested as a co-factor in AIDS dementia syndrome. Lack of an appropriate animal model of natural neurotropic CMV infection has limited understanding of virus entry mechanisms and dissemination in brain. The central hypothesis of this proposal is that systemic CMV infection in immunosuppressed patients disseminates to the brain through specific mechanisms in a predictable, localized pattern and is strongly influenced by the competency of host immune disease. The research described below will define the relationship of systemic CMV infection, host immunity and CNS disease. A novel murine model of parenteral CMV inoculation resulting in neurotropic CMV infection will be used to test this hypothesis through4 primary strategies: 1) determine whether severity of mouse immunodeficiency alters susceptibility to neurotropic CMV dissemination, 2) determine if CMV infection of the CNS can occur through hematogenous dissemination through free virus, infected leukocytes, or directly through intra-axonal transport to brain, 3) determine if mice are protected from neurotropic MCMV by adoptive transfer of specific immune lymphoid cell populations, 4.) determine whether adoptive transfer of immune or non-specific immune T cells can reduce or clear established CMV encephalitis. This proposal elucidates the significance of neurotropic CMV as a principal opportunistic CNS pathogen without confounding variables such as co-incident HIV replication and may help to advance the diagnosis and therapy of CMV related encephalitis and AIDS dementia syndrome. Training inherent to the proposal will extend, broaden, and deepen my knowledge of infectious disease pathogenesis and develop intellectual and technical competency in immune modulation crucial to my scientific independence. Training will be performed at Yale University School of Medicine under the mentorship of Anthony van den Pol, PhD, Professor of Neurosurgery, and a senior neuroscientist, Nancy Ruddle, PhD, Professor of Epidemiology and Public Health/Immunobiology and Epidemiology of Microbial Diseases, and world-class immunologist in collaboration with Akiko Iwasaki, PhD, Assistant Professor of Epidemiology/Public Health who has strong research credentials in the mechanism of host immunity to infectious microorganisms.

K01RR017017

2002-04-01

2008-03-31