The role of Innate Immune receptor, RIG-I, in SARS-CoV2 infection

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Innate immunity is an ancient mechanism present in all cells that serves as an initial defense against a new pathogenic infection. Pathogens are recognized by the innate immunity receptors through specific pathogen associated molecular patterns (PAMPs). Cytosolic, viral RNA are sensed by RIG-I like receptors (RLRs), including RIG-I, melanoma differentiation-associated protein 5 (MDA5), and Laboratory of Genetics and Physiology 2 (LGP2). RIG-I is the prototypical, best-characterized member of the RLR family, consisting of (i) two amino-terminal repeats of the caspase recruitment domain (CARDs) that mediate interactions with signaling proteins; (ii) a central DExD/H box RNA helicase domain required for ATP binding, hydrolysis, and translocation, but not for RNA unwinding; and (iii) a carboxyl-terminal regulatory/repressor domain (RD) essential for viral RNA recognition. Based on our results, a kinetic proofreading pathway was proposed where RIG-I selectively oligomerizes and signals on PAMP RNAs to achieve discrimination beyond differences in binding energies of its ligands. A hyperactive and imbalanced innate immune system results in undesirable autoimmune disorders as well as improper or delayed response to viral infection. For example, Singleton-Merten Syndrome (SMS) is a rare multisystem autoimmune disorder with clinical symptoms, including aortic and valvular calcification, dental anomalies, osteopenia or osteoporosis. Previous studies have reported clinical phenotypes of classic SMS and atypical SMS caused by mutations discovered in MDA5 and RIG-I, indicating that elevated inflammation induced by RLR gain-of-function mutants contributes to the pathogenesis of SMS. We are performing structural and biophysical studies of RIG-I loss-of function-mutants that Dr. Helen Su section has demonstrated are present in some patients with severe COVID-19 disease. These studies will provide a mechanism for how these mutants put persons at risk for severe disease with SARS-CoV-2. We have previously shown the mechanism of how RIG-I senses foreign, viral RNAs and these RIG-I mutants may provide details into why RIG-I is important to reduce the severity of COVID-19 and other viral infections, e.g. influenza virus.