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-Stimulated Antiviral and Immunoregulatory Responses by Blocking Multiple Levels of IFN- Signal Transduction1
Department of Pathology, Ohio State University, Columbus, OH 43210
The type I IFNs represent a primordial, tightly regulated defense
system against acute viral infection. IFN-
confers resistance to
viral infection by activating a conserved signal transduction pathway
that up-regulates direct antiviral effectors and induces
immunomodulatory activities. Given the critical role of IFN- in
anti-human cytomegalovirus (HCMV) immunity and the profound ability
of HCMV to escape the host immune response, we hypothesized that HCMV
blocks IFN--stimulated responses by disrupting multiple levels of
the IFN- signal transduction pathway. We demonstrate that HCMV
inhibits IFN--stimulated MHC class I, IFN regulatory factor-1, MxA
and 2',5-oligoadenylate synthetase gene expression, transcription
factor activation, and signaling in infected fibroblasts and
endothelial cells by decreasing the expression of Janus kinase 1 and
p48, two essential components of the IFN- signal transduction
pathway. This investigation is the first to report inhibition of type I
IFN signaling by a herpesvirus. We propose that this novel immune
escape mechanism is a major means by which HCMV is capable of escaping
host immunity and establishing persistence.
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