Molecular insights into modulation of host innate immune response by viral proteins of RNA viruses SARS-CoV, HCV and Influenza virus

Abstract

One of the first and fast line of defense launched by mammalian hosts to counter virus infection is production of type I interferon (IFN), an innate immune response that generates antiviral state to prevent virus replication and spread by expressing several IFN-stimulated genes. Type I interferon response depends on a set of germ-line encoded receptors called pattern recognition receptors (PRRs) that initiate antiviral signaling upon recognizing distinct pathogen associated molecular patterns (PAMPs). TLR3, RIG-I and MDA5, trigger complex intertwined signaling pathways in response to viral dsRNA leading to the activation of interferon regulatory transcription factors IRF3, IRF7 and NF-κB. These transcription factors mediate inflammatory process to clear virus infection. Viruses can evade host antiviral defenses by using several strategies. SARS coronavirus (SARS-CoV), a highly contagious causative agent of severe acute respiratory syndrome does not induce interferon response suggesting an unknown immune evasive mechanism. My experiments demonstrate that papain-like protease (PLpro) encoded by SARS-CoV is a potent interferon antagonist that functions independent of its protease activity. PLpro directly interacts with IRF-3 preventing its phosphorylation, dimerization, nuclear translocation and thus inhibits type I interferon response triggered by TLR3/RIG-I pathways. Hepatitis C virus is a major blood borne pathogen responsible for 100,000 deaths worldwide annually due to chronic liver cirrhosis. In cell culture normal human hepatocytes are not permissive to HCV replication due to intact TLR3/RIG-I/MDA5 antiviral signaling pathways. However, human hepatoma cells defective in antiviral signal pathways are found to permit HCV replication. My experiments involving reconstitution of functional TLR3 signaling pathways in human heptoma cells demonstrate that TLR3 plays a major role in HCV cellular permissiveness. Finally, my studies with influenza virus NS1 protein demonstrate that NS1 antagonizes the IFN response by blocking RIG-I activation in a strain specific manner. In conclusion, I have made an attempt to understand the complex antiviral signaling pathways at the cellular level in context to three distinct single strand RNA viruses namely, SARS-CoV, HCV and Influenza virus. Though, these viruses are detected by the same set of PRRs to trigger antiviral signaling, the mechanism by which they evade antiviral response appears to be distinct.