The paramyxovirus family includes emerging viruses such as Hendra virus and Nipah virus as well as many important human and animal pathogens, such as respiratory syncytial virus, measles virus, mumps virus and Newcastle disease virus. Apoptosis play an important role in the pathogenesis of paramyxoviruses, but the mechanisms of activation and inhibition of apoptotic pathways by paramyxoviruses are not well understood. Simian virus 5 (SV5), a paramyxovirus, does not cause apoptosis but a mutant SV5 without the 44-amino-acid-residue small hydrophobic (SH) gene (rSV5deltaSH) induces apoptosis. In preliminary studies, increased expression levels of tumor necrosis factor alpha (TNF) were detected in rSV5deltaSH-infected cells and TNF played an essential role in inducing apoptosis. It is hypothesized that the SH protein blocks TNF-induced apoptotic pathways and the SH protein may define a new anti-apoptosis mechanism. The long-term goal of this work is to understand how paramyxoviruses interact with host cell apoptotic pathways. The proposal focuses on following aims: (1) investigate the mechanism of inhibition of TNF signaling pathways by the SH protein. In preliminary studies, the SH protein was sufficient to inhibit TNF signaling. Key residues of SH that are important for its inhibitory effect and host cell proteins with which SH interacts will be identified; (2) investigate the mechanism of activation of TNF expression in rSV5deltaSH-infected cells. Expression of TNF in virus-infected cells will be examined at the mRNA and protein levels. SV5 proteins responsible for activating expression will be identified; (3) study anti-apoptosis functions of SH proteins encoded by other paramyxoviruses. SV5 containing SH genes from other paramyxoviruses in place of the SH gene of SV5 will be generated and examined for their abilities to induce apoptosis. Understanding the roles played by viral proteins in activating and inhibiting apoptosis will provide new insights on paramyxovirus pathogenesis and may lead to new targets for anti-viral therapy and new strategies for vaccine development. ? ? ?
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