Understanding host-viral interaction is an essential step in developing safe and effective antimicrobials against biodefense agents and emerging pathogens. Early detection of invading viruses by the host depends on a limited number of specific intracellular receptors that detect viral patterns and activate signal transduction cascades, thereby triggering interferon (IFN)-mediated anti-viral defense mechanisms. Retinoic acid-inducible gene I (RIG-I) has emerged as a key cytosolic viral RNA receptor for sensing emerging viruses, including the influenza virus and hepatitis virus C (HCV). In addition, members of the tripartite motif (TRIM) protein family, containing a RING-finger domain, B box/coiled-coil domain (B Box/CCD), and a SPRY domain, play a major role in the inhibition of the lifecycles of viruses. Furthermore, the interconnection between the RIG-I and TRIM family is required to initiate the induction of the protective IFN-mediated host anti-viral innate immunity. Our collaborative works have demonstrated that the RIG-Imediated IFN pathway requires multiple step processes: upon viral infection, the C-terminal """"""""regulatory"""""""" domain (RD) of RIG-I recognizes viral RNA in a 5'-triphosphate-dependent manner, leading to RIG-I dimerization and ATPase activity. Subsequently, RIG-I undergo a robust ubiquitination induced by the TRIM25 E3 ligase, enabling RIG-I to interact with the downstream CARD-containing mitochondrial anti-viral signaling (MAVS) protein and thereby inducing antiviral signal transduction to limit viral replication and transmission. The goal of this study focuses on better understanding the regulation of RIG-I and TRIM25 pathways: how posttranslational modifications affect RIG-I and TRIM25 signaling activity (Aim 1), what the modes of feedback regulation for the RIG-I and TRIM25 pathways are (Aim 2), and finally, what roles RIG-I and TRIM25 mediated immune surveillance have against viruses (Aim 3). Thus, the proposed study will attempt to delineate the molecular mechanisms underlying the host-viral interaction at a basic scientific level and will also provide the foundations for developing novel diagnostic and therapeutic strategies for emerging virus-associated disorders at the public health level.
Understanding of host-viral interaction is an essential step to develop safe and effective antimicrobials against biodefense agents and emerging pathogens. RIG-I and TRIM protein family play major roles in the inhibition of lifecycles of viruses. The proposed study is targeted to delineate the molecular mechanism underlying the host-viral interaction, with a specific focus on the RIG-I- and TRIM25-mediated IFN response.
|Pisanelli, Giuseppe; Laurent-Rolle, Maudry; Manicassamy, Balaji et al. (2016) La Piedad MichoacÃ¡n Mexico Virus V protein antagonizes type I interferon response by binding STAT2 protein and preventing STATs nuclear translocation. Virus Res 213:11-22|
|Nelson, Emily V; Schmidt, Kristina M; DeflubÃ©, Laure R et al. (2016) Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions. J Virol 90:7268-84|
|Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, BÃ©atrice et al. (2015) Human intracellular ISG15 prevents interferon-Î±/Î² over-amplification and auto-inflammation. Nature 517:89-93|
|Lee, Jiyoung; Tian, Yongjun; Chan, Stephanie Tze et al. (2015) TNF-Î± Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism. PLoS Pathog 11:e1004937|
|Zhang, Jichuan; Fei, Jingyi; Leslie, Benjamin J et al. (2015) Tandem Spinach Array for mRNA Imaging in Living Bacterial Cells. Sci Rep 5:17295|
|Riegger, David; Hai, Rong; Dornfeld, Dominik et al. (2015) The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. J Virol 89:2241-52|
|Tian, Y; Kuo, C-F; Sir, D et al. (2015) Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ 22:1025-34|
|Weber, Michaela; Sediri, Hanna; Felgenhauer, Ulrike et al. (2015) Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 17:309-19|
|Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47|
|Buskiewicz, Iwona A; Koenig, Andreas; Roberts, Brian et al. (2014) c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3. PLoS One 9:e96156|
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