Evasion of RIG-I/MDA5 and TLR3-mediated innate immunity by hepatitis A virus

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Title: Evasion of RIG-I/MDA5 and TLR3-mediated innate immunity by hepatitis A virus
Author: Lin Qu
Abstract: Since the identification of several families of pattern recognition receptors (PRRs ) , their roles in the innate immune system and how they are regulated by the invading pathogens have been the subjects of extensive research . Cellular helicases RIG -I and MDA5 , and Toll -like receptor 3 (TLR3 ) are PRRs that detect virus -specific double stranded RNA (dsRNA ) . Activation of these PRRs by dsRNA lead to their interaction with adaptor proteins , which engage downstream kinases to activate two critical transcription factors , NF -kB and IRF3 , in the induction of type I interferons (IFNs ) and IFN -stimulated genes (ISGs ) that ultimately establish an antiviral state . These signaling pathways are central to host antiviral defense and thus become targets for viral interference . Hepatitis A virus (HAV ) , a hepatotropic picornavirus , is capable of blocking IRF3 activation and type I IFN expression in cell culture , but the exact mechanism (s ) remains undefined . Our studies revealed that HAV disrupts RIG -I /MDA5 -mediated induction of type I IFN through proteolysis of MAVS , a mitochondrial -localized adaptor of RIG -I and MDA5 , by the viral 3ABC protease precursor . The 3ABC cleavage of MAVS requires both the protease activity of 3Cpro and a transmembrane domain in 3A that directs 3ABC to mitochondria . The signaling ability of MAVS depends on its mitochondrial localization ; cleavage of MAVS by 3ABC removes MAVS from mitochondia , thus abolishing its adaptor function . We also demonstrated that the parallel , yet independent , TLR3 signaling pathway is also inhibited by HAV through cleavage of the adaptor protein TRIF by the 3CD protease -polymerase precursor . Cleavage of TRIF by 3CD requires both the protease activity of 3Cpro and the 3Dpol moiety , but not the 3Dpol polymerase activity , in an “in cis” manner . This research also revealed a unique order of processing in the 3CD cleavage of TRIF , and an unexpected role of the 3Dpol domain in modulating the substrate specificity of 3CD that allows it to cleave non -canonical 3Cpro cleavage sites within TRIF . The data generated in this dissertation provide two major mechanisms by which HAV evades innate immune responses , and extend our understanding of the signaling pathways of the innate immune system .
URI: http : / /hdl .handle .net /2152 .3 /179
Date: 2010-06-18

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Evasion of RIG-I/MDA5 and TLR3-mediated innate immunity by hepatitis A virus. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /179 .

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