The host innate immune response, initiated by the sensing of non-self viral nucleic acid, determines the outcome of most diseases resulting from viral infection. Therefore, in order to effectively combat viral diseases, it is necessary to critially understand the control mechanisms of the innate immune responses. We have discovered that interferon (IFN)-stimulated gene Oligoadenylate Synthetase-like (OASL) can differentially control the host response against RNA and DNA viruses. This proposal will test the hypothesis that OASL differentially modulates the sensitivity and the outcome of innate immune signaling against RNA and DNA viruses and determine the distinct molecular mechanisms by which OASL controls innate immune signaling in vitro and in vivo. We have found that human OASL sensitizes the RNA-sensor, RIG-I by mimicking one of the RIG-I ligand polyubiquitin. Thus, OASL enhances RIG-I-signaling-mediated IFN induction, and exerts a strong antiviral activity against multiple RNA virus infections. Consequently, genetic ablation of OASL in human cells, or Oasl2 in mice reduces RIG-I-mediated IFN induction and enhances susceptibility to various RNA virus infection (Zhu et al. 2014, Immunity. 40:936-48). On the other hand, the OASL or Oasl2-deficient cells show enhanced IFN response to DNA-sensor, cGAS activation, and consequent lower DNA virus replication. Our initial results indicate that OASL through its direct interaction with cGAS, may negatively regulate the cGAS signaling. As some of the DNA viruses establish long-term infections, one of the major significances of this negative regulation of cGAS signaling by OASL can be to restrict inflammation during DNA virus infections. The goal of this proposal is to determine the molecular mechanisms of OASL-mediated modulation of innate immune signaling through three independent specific aims: (1) determine the molecular mechanism of RIG-I signaling enhancement, and changes of RIG-I properties by OASL; (2) determine the mechanisms and consequences of OASL-mediated modulation of IFN induction through the DNA-sensor cGAS; and (3) define the in vivo role of OASL in antiviral responses using two model RNA (VSV) and DNA (HSV) viruses. Thus, this study highlights the unique activity of human OASL and determines the mechanistic basis of its function that will guide the future development of therapeutic strategies against specific virus infection by targeting the OASL-pathway.

Public Health Relevance

Host innate immune response plays a crucial role in combating a large number of viral infections. This proposal focuses on the very early part of this host response, and is geared towards understanding its controls using a novel innate immune protein - OASL. The OASL protein can uniquely control the host response to virus infections either positively or negatively depending on the virus. When completed, our studies will offer a new paradigm for developing novel antiviral strategies by boosting the body's natural antiviral immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI118896-04
Application #
9451225
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2015-04-15
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
McCormick, Kevin D; Ghosh, Arundhati; Trivedi, Sumita et al. (2016) Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous cell carcinoma. Carcinogenesis 37:522-9
Cuevas, Rolando A; Ghosh, Arundhati; Wallerath, Christina et al. (2016) MOV10 Provides Antiviral Activity against RNA Viruses by Enhancing RIG-I-MAVS-Independent IFN Induction. J Immunol 196:3877-86
Dhar, Jayeeta; Cuevas, Rolando A; Goswami, Ramansu et al. (2015) 2'-5'-Oligoadenylate Synthetase-Like Protein Inhibits Respiratory Syncytial Virus Replication and Is Targeted by the Viral Nonstructural Protein 1. J Virol 89:10115-9
Ibsen, Mikkel S√łes; Gad, Hans Henrik; Andersen, Line Lykke et al. (2015) Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling. Nucleic Acids Res 43:5236-48