Molecular mechanisms of mouse adenovirus type 1 pathogenesis
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Both viral genes and host factors contribute to the final outcome of mouse adenovirustype 1 (MAV-1) infection. MAV-1 early region 1A (E1A) encodes a virulence gene in viralinfection of mice. An unbiased experimental approach, a GST pull-down, was used to screen forcellular proteins that interact with E1A protein. We identified mouse Sur2 (mSur2), a subunit ofMediator complex, as a protein that binds to MAV-1 E1A. Conserved region 3 (CR3) of MAV-1E1A was mapped as the region required for Sur2-E1A interaction. Studies on the functions ofSur2 using mouse embryonic fibroblasts (MEFs) showed that there was a multiplicity-dependent-/-+/+growth defect of MAV-1 in Sur2 MEFs compared to Sur2 MEFs. The viral replication-/-defects in Sur2 MEFs appeared to be due at least in part to a defect in viral early genetranscription.Further study of the contributions of E1A to mSur2 function in MAV-1 replication usingE1A mutant viruses suggests that mSur2 functions through E1A CR3 interaction-dependent and-independent pathways in cell culture. Moreover, titrations of viral yields from infected brains offour inbred strains of mice showed that E1A null (pmE109) and CR3” (dlE106) mutant viruseshad a significant defect in viral replication compared to wt MAV-1 in all these strains of mice.This result supports the hypothesis that MAV-1 E1A-mSur2 interaction is important in MAV-1replication in mice.MAV-1 infects only brain microvascular endothelial cells (ECs), and causes dose-dependent encephalomyelitis and inflammatory cell accumulation in the brain blood vessels. Theexpression of cell adhesion molecules such as ICAM-1, VCAM-1, and E-selectin on ECsmediates the adhesion and permeation of lymphocytes and leucocytes into the inflammatorylesions. The expression levels of VCAM-1, ICAM-1, and E-selectin were tested on oneestablished cell line, mouse brain microvascular endothelial cells (MBMECs). Wt MAV-1infection did not alter expression of these cellular adhesion molecules, whereas cytokines TNF-±and IFN-³ induced VCAM-1 and ICAM-1 expression. Our data suggest that MAV-1 infectionmay not directly induce the expression of cellular adhesion molecules on endothelial cells inmouse brain, but could do so through an indirect mechanism, such as by inducing cytokineexpression.