Key components of the host innate immune response are pattern recognition receptors (PRRs) that sense conserved structural components of viral pathogens and subsequently activate signaling cascades leading to effective antiviral defense mechanisms. RIG-I and MDA5, members of the RIG-I-like receptor (RLR) family, are key cytosolic receptors for sensing various RNA viruses, including influenza virus, paramyxoviruses, and dengue virus. Upon binding of viral RNA, RLRs initiate signal transduction that results in type-I interferon (IFN) gene expression to suppress viral replication and the spread of infection. For their efficient replication, however, viruses have evolved elegant strategies to evade the IFN-mediated host immune response. Despite the recent progress in deciphering molecular components in the RLR pathway, the regulation of RLR-induced immune signaling remains largely undetermined; however, it is exactly the regulation of host immunity which dictates the outcome of the viral infection and disease. The proposed study will build upon a recent discovery made by the Gack laboratory that the cellular phosphatases PP1?/? are essential activators of RLR signal transduction. PP1?/? are recruited to RIG-I and MDA5 upon viral infection and induce RLR dephosphorylation, promoting antiviral signaling. Virus replication studies demonstrated that PP1?/? are required for an effective type-I IFN response to paramyxoviruses, influenza virus, picornaviruses, and dengue virus. Furthermore, our most recent study revealed that several members of the paramyxovirus family target PP1?/? to evade immune surveillance by MDA5. Molecular, biochemical, and cell biological approaches combined with virus infection studies will focus on defining in precise detail how the phosphatase PP1 activates RLR- mediated antiviral signaling (Aim 1). This study will also give detailed insights into the mechanisms by which viruses counteract PP1 and thereby RLR-mediated immunity, and further determine the physiological role of this novel immune escape strategy in IFN antagonism and virus replication (Aim 2). Insights gained from this study will not only illuminate new views on immune regulatory networks, but also identify novel host-virus interactions, thereby providing the foundation for developing novel therapeutic strategies for emerging virus-associated disorders.

Public Health Relevance

Infection by emerging viruses, such as influenza, HIV, measles, and dengue viruses, poses a major challenge to global health. This study will delineate the molecular mechanisms of how infected cells detect viral infection and initiate signal transduction to induce antiviral defense mechanisms. Furthermore, this study will give detailed insights into innate immune evasion by measles virus and related viruses, which may ultimately contribute to the establishment of novel therapeutic approaches for virus-associated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI087846-08
Application #
9388300
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Park, Eun-Chung
Project Start
2010-04-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Chiang, Cindy; Gack, Michaela U (2017) Post-translational Control of Intracellular Pathogen Sensing Pathways. Trends Immunol 38:39-52
Sparrer, Konstantin M J; Gableske, Sebastian; Zurenski, Matthew A et al. (2017) TRIM23 mediates virus-induced autophagy via activation of TBK1. Nat Microbiol 2:1543-1557
Chan, Ying Kai; Gack, Michaela U (2016) Viral evasion of intracellular DNA and RNA sensing. Nat Rev Microbiol 14:360-73
Chan, Ying Kai; Gack, Michaela U (2016) A phosphomimetic-based mechanism of dengue virus to antagonize innate immunity. Nat Immunol 17:523-30
Sanchez, Jacint G; Chiang, Jessica J; Sparrer, Konstantin M J et al. (2016) Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway. Cell Rep 16:1315-1325
Gack, Michaela U; Diamond, Michael S (2016) Innate immune escape by Dengue and West Nile viruses. Curr Opin Virol 20:119-128
Sparrer, Konstantin M J; Gack, Michaela U (2015) Intracellular detection of viral nucleic acids. Curr Opin Microbiol 26:1-9
Chan, Ying Kai; Gack, Michaela U (2015) RIG-I-like receptor regulation in virus infection and immunity. Curr Opin Virol 12:7-14
Carocci, Margot; Hinshaw, Stephen M; Rodgers, Mary A et al. (2015) The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob Agents Chemother 59:85-95
Davis, Meredith E; Gack, Michaela U (2015) Ubiquitination in the antiviral immune response. Virology 479-480:52-65

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