Pathogenesis of murine cytomegalovirus infection in neonatal mice

Cytomegalovirus (CMV) infections are a major cause of morbidity and mortality in congenitally and perinatally- infected infants. Despite the extensive characterisation of clinical disease induced by human CMV in neonatal infections in humans, fundamental questions regarding the pathogenesis of disease remain unanswered. For example , which tissues suport virus replication and what is the nature of tissue damage? What is the role of immune response and cytokines in protection from or exacerbation of disease? Also, which viral determinants are essential to virulence and how does at acquisition influence virulence? To begin to adress these issues, we have establishes a model of disease in neonatal mice using both virulent and attenuated strains of murine CMV. Our aproach to the study of MCMV pathogenesis in newborns is was a comparative one, in which infection with tissue culture derived virus was compared with an attenuated recombinant mutant lacking the fcr gene product. Investigation of MCMVpathogenesis in neonatal mice revealed several important aspects of disease. First, neonatal infection with WT virus followe a virulent disease course involving multiple tissues and organs. Absence of fcr gene product, however, results in significant attenuation of disease course. Second, virus replication and damage in the brain and meminges was a primary feature of infection and was unique to newborn mice. Third, this study implicates immunopathological mechanisms of disease booth in the CNS (neurovirulence), and in peripheral tissues and organs, especially the heart and conective tissues. In adition to morphological evidencesupporting immunopathology in neonatal infections, the dramatic induction of TNF-aassociated with the virulent WT virus also supports an immunopathological condition occuring in these mice