Viral diseases are a major burden to the society and more effective prevention and cure require a better understanding of the host immune systems that usually protect us from these diseases. For combating virus infection, the interferon system is the most important component of the mammalian innate immune system. Interferons induce many cellular genes, some of which mediate their antiviral effect. Among these genes are the members of the interferon-stimulated gene (ISG) 56 family, four in human and three in mouse, which are also induced directly by double-stranded RNA and virus infection. Our ongoing studies indicate that different members of this family are not always coordinately induced and they have distinct antiviral and cellular functions. This proposal is to delineate their induction pathways and to determine their antiviral, cellular and physiological functions.
Three specific aims will be pursued for this purpose. In the first aim, we will determine the molecular basis of the observed differential induction of the three mouse ISG56 family members in response to different inducers in kidney mesangial cells, B cells and plasmacytoid dendritic cells. In the second aim we will determine the mechanism of inhibition of human papilloma virus (HPV) replication by human P56, the product of ISG56. For this purpose, we will investigate the exact functions of the viral E1 protein that are inhibited by P56 and delineate the nature of the structural interaction between E1 and P56. Moreover, we will assess the role of P56 in mediating interferon's antiviral action against HPV. In the third aim, we will investigate the roles of the three mouse proteins in pathogenesis by the neurotropic RNA viruses, West Nile virus and neurotropic coronavirus. For this purpose, we will generate a number of conditional knock-out mouse models that lack a single, combinations, or all members of the ISG56 family of genes. Our proposed study will not only address the above specific aims but also generate valuable reagents, such as knock-out mouse models, for many scientists who study pathogenesis by other viruses.

Public Health Relevance

Viral diseases are a major burden to the society and more effective prevention and cure require a better understanding of the host immune systems that usually protect us from these diseases. For combating virus infection, the interferon system is the most important component of the mammalian innate immune system and here we propose to study its functions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068782-26
Application #
8444641
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1985-09-30
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
26
Fiscal Year
2013
Total Cost
$409,382
Indirect Cost
$148,629
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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 20:329-41
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
Fensterl, Volker; Chattopadhyay, Saurabh; Sen, Ganes C (2015) No Love Lost Between Viruses and Interferons. Annu Rev Virol 2:549-72
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; Sen, Ganes C (2015) Interferon-induced Ifit proteins: their role in viral pathogenesis. J Virol 89:2462-8
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Meet the terminator: The phosphatase PP2A puts brakes on IRF-3 activation. Mol Cell 54:210-1
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
Fensterl, Volker; Wetzel, Jaime L; Sen, Ganes C (2014) Interferon-induced protein Ifit2 protects mice from infection of the peripheral nervous system by vesicular stomatitis virus. J Virol 88:10303-11
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Tyrosine phosphorylation in Toll-like receptor signaling. Cytokine Growth Factor Rev 25:533-41
Chattopadhyay, Saurabh; Sen, Ganes C (2014) dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res 34:427-36

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