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| innate immunity | |
 The
Innate Immune SystemOne of the first defenses against infecting pathogens is the innate immune system. Against incoming viruses, induction of the interferon (IFN) system leads to the establishment of an antiviral state in the cell. Cellular recognition of viral products such as viral RNA or double-stranded RNA by Toll-like receptors (TLR3,7,8,and 9), or cytoplasmic sensors such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), leads to induction of IFN-ß transcription. IFN-ß signals in an autocrine and paracrine fashion to induce IFN-α, which in turn induces a plethora of IFN-stimulated genes encoding proteins with antiviral functions. In turn, viruses have evolved means of evading, or directly countering, IFN induction by encoding IFN antagonists such as the influenza virus NS1 protein, arenavirus nucleoprotein, and flavivirus non-structural proteins. As a result, the host-virus struggle has been waged on an evolutionary scale. Influenza NS1 The influenza non-structural protein NS1 exerts inhibitory properties at least in part by binding to double-stranded RNA (dsRNA), resulting in sequestration of the retinoic acid-inducible gene I (RIG-I), which is a cellular sensor of RNA virus infection. The NS1 protein of influenza A virus binds to RIG-I and inhibits downstream activation of IFN response factor-3 (IRF-3), blocking the transcriptional induction of IFN-ß. NS1 also binds and inhibits the cleavage and polyadenylation specificity factor (CPSF) component of the cellular pre-mRNA processing machinery, a function which may augment IFN antagonism. We are further studying the mechanisms by which NS1 blocks IFN induction. Mouse-adapted influenza virus with an NS1 defective in RNA-binding is attenuated and induces high levels of IFN-ß. Thus, we are examining the interplay of the NS1 protein with the host immune system in vivo to understand the consequences, duration and degree of IFN response resulting from infection by different strains of influenza A virus. IFN-ß induction is a well-characterized transcription induction system. Despite this knowledge, many aspects of IFN-ß induction remain obscure. We have determined the structure of the enhanceosome, the IFN-ß pretranscriptional complex. In addition, we are modeling the integration of signals that lead to IFN-ß induction and effects of antagonists such as influenza NS1 and arenavirus NP proteins. Arenaviruses Arenaviruses include the lymphocytic choriomeningitis virus (LCMV) and clinically relevant viruses that are causative agents of hemorrhagic fever in humans. LCMV serves as a tractable model system to study acute and persistent viral infections. Using LCMV, we found that the viral nucleoprotein (NP) inhibits the IFN response in infected cells by blocking the activation of IRF-3. This is the first nucleoprotein described to block production of type I IFN during viral infection as well as the first member of the Arenaviridae family described to counteract the type I IFN response. Furthermore, New World viruses among the Arenaviridae that are capable of causing hemorrhagic fever (Junin and Machupo viruses) conserve the IFN antagonist activity of NP proteins. L. MARTÍNEZ-SOBRIDO, P. GIANNAKAS, B. CUBITT, A. GARCÍA-SASTRE & J.C. DE LA TORRE: Differential inhibition of type I interferon induction by arenavirus nucleoproteins. Journal of Virology, 81, 12696-12703 (2007). G. KOCHS, A. GARCÍA-SASTRE & L. MARTÍNEZ-SOBRIDO: Multiple anti-interferon actions of the influenza A virus NS1 protein. Journal of Virology, 81, 7011-7021 (2007). M. MIBAYASHI, L. MARTINEZ-SOBRIDO, Y.M. LOO, W.B. CARDENAS, M. GALE JR. & A. GARCÍA-SASTRE: Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. Journal of Virology, 81, 514-524 (2007). C.R. ESCALANTE, E. NISTAL-VILLÁN, L. SHEN, A. GARCÍA-SASTRE & A.K. AGGARWAL: Structure of IRF-3 bound to the PRDIII-I regulatory element of the human interferon-beta enhancer. Molecular Cell, 8, 703-716 (2007). A. GARCÍA-SASTRE & C.A. BIRON: Type 1 interferon and the virus-host relationship: A lesson in détente. Science, 312, 879-882 (2006). L. MARTÍNEZ-SOBRIDO, E.I. ZÚÑIGA, D. ROSARIO, A. GARCÍA-SASTRE & J.C. DE LA TORRE: Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus. Journal of Virology, 80, 9192-9199 (2006). Spotlight article and highlighted by the journal. L. MARTÍNEZ-SOBRIDO & A. GARCÍA-SASTRE: Virus complementation assays to identify interferon antagonists. In "Viral Immunity. Methods and Protocols", R. Donis & J.M. Katz (Eds.), Humana Press Inc. (2006). N. DONELAN, C.F. BASLER & A. GARCÍA-SASTRE: A recombinant influenza A virus expressing an RNA-binding defective NS1 protein induces high levels of IFN-ß and is attenuated in mice. Journal of Virology, 77, 13257-13266 (2003). J. TALON, C.M. HORVATH, R. POLLEY, C.F. BASLER, T. MUSTER, P. PALESE & A. GARCÍA-SASTRE: Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. Journal of Virology, 74, 7989-7996 (2000). |
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