MUCOSAL INFECTION WITH ARENAVIRUS

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Arenaviruses are rodent-borne viruses that cause fatal illness when transmitted to man. Lassa fever virus in Africa and Machupo virus in Bolivia are two arenaviruses that have caused noteable outbreaks in the last few years. The prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), has frequently been used to study cell-mediated immunity in inbred mice. However murine infection is an inappropriate model for arenavirus disease in man, because human disease is more virulent and has a different pathogenic mechanism. Furthemore, experimental infections have employed primarily parenteral routes of inoculation, and mucosal inoculation (through inhalation or ingestion) is the most frequent natural route of infection. Studies with other viral systems, particularly the monkey model for AIDS, illustrate that the route of inoculation profoundly influences the pathogenesis and immune responses to infection. Since little is known about arenavirus infection after mucosal inoculation, we propose a pilot study to extend our murine mucosal studies to the nonhuman primate. After intragastric inoculation of rhesus macaques we will collect information about the level and distribution of virus, the timecourse of immune responses, and the progression of pathology. We will employ LCMV infection of monkeys, which strongly resembles Lassa fever virus infection of monkeys. We will test the hypothesis that mucosal LCMV infection of the rhesus macaque shares several features of murine mucosal LCMV infection, but differs fundamentally in pathogenesis. The information we collect will be important for human disease and for diseases affecting nonhuman primates (e.g., callitriched hepatitis, an emerging disease of captive New World primates). The information about immune response timecourse will provide landmarks for vaccine-elicited immune responses. Thus, this information will serve as the basis for developing mucosal vaccines and pharmacological treatments that target mucosal arenavirus infections.