Humans cytomegalovirus (CMV) has been implicated in the pathogenesis of numerous clinical syndromes in man. CMV is known to infect 1% of all human newborns, and antibody studies among adults indicate prior CMV infection has occurred in 50 to 80%. With respect to the nervous system, CMV exerts its greatest effect upon the developing fetus or infant, and survivors of congenital CMV infection typically have serious central nervous system abnormalities. Not only may CMV cause considerable morbidity and mortality as a primary pathogen, CMV infection in humans has been associated with an increased incidence of secondary fungal and bacterial infections, including bacterial meningitis. This association occurs in organ transplant recipients and in young children, and has been attributed to the widespread effects of CMV infection upon host defense mechanisms. This proposal outlines a four year project which will investigate the effects of CMV infection upon the acquisition and pathogenesis of bacterial meningitis utilizing an animal model of combined infection with murine cytomegalovirus (MCMV) and bacterial pathogens. The objectives include determination of 1) the effects of MCMV infection upon mortality and severity of bacterial infection during combined infection with MCMV and bacterial pathogens, 2) the effects of MCMV infection upon the pathogenesis of bacterial meningitis, and 3) the effects of MCMV infection upon host defense mechanisms. These objectives will be accomplished by establishing MCMV infection of mice via intraperitoneal routes and by challenging MCMV-infected animals with intranasal inocula of bacterial pathogens. The occurrence and severity of bacterial meningitis will be assessed by bacteriologic and histopathologic examination of the murine nervous system. Investigation of host defense mechanisms will focus upon the direct and indirect effects of MCMV infection upon neutrophil function, including chemotaxis, bacterial phagocytosis, and bacterial killing. In addition, neutrophils from MCMV-infected animals will be studied for evidence of MCMV infection by light and electronmicroscopic examination and by immunofluorescent localization of MCMV antigen. The studies proposed here should be directly relevant to combined infections with CMV and other microorganisms in humans, and should provide additional insights into the role of virus-induced alterations of host defense mechanisms in the pathogenesis of human bacterial infection.
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