The goal of the project is to investigate how a newly discovered antiviral pathway is activated and regulated and what its role is in determining viral pathogenesis and persistence. The type I interferon (IFN) system plays a major role in innate antiviral response. Virus infection activates the transcription factor IRF-3, which is responsible for the induction of IFN and other antiviral proteins. Recent investigation by us has revealed that IRF-3 also activates an IFN-independent pro-apoptotic pathway, named RIPA (RIG-I-activated IRF-3-mediated Pathway of Apoptosis). To trigger RIPA, activated IRF-3 binds Bax and translocates it to mitochondria to cause apoptosis;the two functions of IRF-3 are genetically separable. RIPA is activated by many RNA and DNA viruses and inhibits both viral replication and pathogenesis. RIPA is temporally regulated through the action of XIAP and PI3 kinase, which is also activated upon virus infection. In the absence of RIPA, viruses establish persistent infection. Here we propose to investigate RIPA further.
In Aim 1, we will investigate how IRF-3 is activated in RIPA as a consequence of phosphorylation of specific serine residues and ubiquitynation of specific lysine residues. Genetic and biochemical analyses will be used for this purpose.
In Aim 2, we will investigate how viruses evade RIPA temporarily, by triggering negative regulation of RIPA though activation of the epidermal growth factor receptor, which in turn activates PI3 kinase.
In Aim 3, we will investigate the physiological relevance of RIPA in determining the outcome of virus infection. Mutant cells defective in one, but not the other, action of IRF-3, will be used for measuring the role of RIPA on the efficiency of virus replication and establishing viral persistence. Finally, genetically modified mice, including new IRF-3 mutant knock-in mice which have been generated for this project, will be used to assess the in vivo contribution of RIPA in controlling viral pathogenesis.

Public Health Relevance

Because viral diseases are major health risks to the society, it is important to understand how they are caused and how our natural defense mechanisms can protect us. A virus-infected cell can be productively infected and produce a large number of infections progeny viruses;hence, an effective antiviral strategy, for the host, is to promote death of the infected cell before it produces more viruses. This proposal is to investigate how such suicidal response of the infected cell is triggered and regulated.

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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