Because viral diseases are major health risks to the society, it is important to understand how they are caused and how our natural defense systems can protect us. A virus-infected cell can either die or it can live; if it lives it may be permanently infected with the virus. This proposal is to investigate the molecular mechanism that dictates the above choice, namely, whether a virus-infected cell dies or lives and produces more viruses. Many major viral diseases are caused by Paramyxoviridae, such as respiratory syncytial virus, parainfluzenza virus, measles virus and mumps virus. The nature and the severity of pathogenesis is determined by the host response, a major component of which is the innate response of the infected cell which may undergo apoptosis or live and be capable to establish persistent infection, the two outcomes having opposite effects on the host organism. We have made the novel observation that in cells not expressing the cellular transcription factor IRF-3, paramyxoviruses are not lytic because IRF-3 initiates an apoptotic response in infected cells. Moreover, this response is greatly accelerated by inhibiting the activity of PI3 kinases. These observations led us to formulate the hypothesis that IRF-3 determines the choice between lytic and non-lytic infection and PI3 kinases determine the timing of the lysis.
Three specific aims will be pursued to test the hypothesis. In the first aim, we will determine which known properties of IRF-3 are needed and which known IRF-3 regulated genes may be mediating apoptosis. These experiments will use over- expression of individual proteins or their ablation by siRNA. Finally, unbiased genetic screens of the whole human genome will be conducted by using insertional mutagenesis or an appropriate shRNA library and cell survival as the end point assay. In the second aim, we will determine whether the intrinsic or the extrinsic pathway is used in viral apoptosis. We will also identify the specific isozyme of PI3 kinase and its downstream targets that are required for blocking the rapid apoptosis. In the third aim, we will compare the properties of the persistently infected cell with those of the acutely infected cells. For this purpose, the different steps of the viral life cycle will be examined. Moreover, the status of the innate immune response in the persistently infected cells will be evaluated. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Cassetti, Cristina
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Chattopadhyay, Saurabh; Sen, Ganes C (2017) RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA): a new antiviral pathway. Protein Cell 8:165-168
Wang, Xin; Majumdar, Tanmay; Kessler, Patricia et al. (2016) STING Requires the Adaptor TRIF to Trigger Innate Immune Responses to Microbial Infection. Cell Host Microbe 20:329-341
White, Christine L; Kessler, Patricia M; Dickerman, Benjamin K et al. (2016) Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members. J Biol Chem 291:13535-45
Chattopadhyay, Saurabh; Kuzmanovic, Teodora; Zhang, Ying et al. (2016) Ubiquitination of the Transcription Factor IRF-3 Activates RIPA, the Apoptotic Pathway that Protects Mice from Viral Pathogenesis. Immunity 44:1151-61
Fensterl, Volker; Sen, Ganes C (2015) Interferon-induced Ifit proteins: their role in viral pathogenesis. J Virol 89:2462-8
Majumdar, Tanmay; Chattopadhyay, Saurabh; Ozhegov, Evgeny et al. (2015) Induction of interferon-stimulated genes by IRF3 promotes replication of Toxoplasma gondii. PLoS Pathog 11:e1004779
Fensterl, Volker; Chattopadhyay, Saurabh; Sen, Ganes C (2015) No Love Lost Between Viruses and Interferons. Annu Rev Virol 2:549-72
Wetzel, Jaime L; Fensterl, Volker; Sen, Ganes C (2014) Sendai virus pathogenesis in mice is prevented by Ifit2 and exacerbated by interferon. J Virol 88:13593-601
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Meet the terminator: The phosphatase PP2A puts brakes on IRF-3 activation. Mol Cell 54:210-1
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Tyrosine phosphorylation in Toll-like receptor signaling. Cytokine Growth Factor Rev 25:533-41

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