 Ph.D. (2000) |
Luis
Martinez-Sobrido
Assistant Professor of Microbiology & Immunology Primary Appointment: GEBS Cluster Affiliations: |
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| Contact Information | ||
| University of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 672 Rochester, NY 14642 |
KMRB 3-9615 Phone: (585) 275-3402 Fax: (585) 473-9573 E-Mail: luis_martinez@urmc.rochester.edu |
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- Research Focus
- Evasion of the innate immune response by viruses.
- Research Overview
- Type I Interferon (IFN) plays an important key role in the host antiviral innate immune response. For that reason, viruses have developed a plethora of strategies to disrupt the IFN mediated antiviral defense of the host, and viral gene products responsible for these disruptions are often major virulence determinants. Viruses have developed a variety of mechanisms to subvert the host IFN response at diverse levels, including blocking IFN induction and its signaling, or interfering with the action of the host antiviral gene products induced by IFN. My current projects focus, mainly, on Arenaviruses and Influenza viruses.
- Arenaviruses merit significant interest as clinically important human pathogens, including several causative agents of hemorrhagic fever disease. Using Lymphocytic Choriomeningitis Virus (LCMV), the prototype member in the family, we found that the viral nucleoprotein (NP) inhibits the IFN response in infected cells by interfering with the activation of the Interferon Regulatory Factor 3 (IRF3). This was the first nucleoprotein described to block production of Type I interferon during viral infection as well as the first member of the Arenaviridae family described to counteract the Type I IFN response. My work focuses, now, to characterize the anti-IFN properties of LCMV-NP as well as the implications of this function during viral replication.
- Influenza viruses are globally important human pathogens that affect up to 500 million people annually. During the effective replication cycle of the virus in its hosts, Influenza non-structural protein 1 (NS1) has been demonstrated to perform several important functions. One of the best characterized functions is the ability of Influenza NS1 to antagonize Type I IFN production, preventing an antiviral state in the host. My previous work has shown that Influenza NS1 exerts its inhibitory properties at least in part by its binding to double-stranded RNA (dsRNA), resulting in the sequestration of the retinoic acid-inducible gene I (RIG-I), a cellular sensor of RNA virus infection, therefore inhibiting IRF3 activation. In addition to blocking the activation of IRF3, Influenza NS1 has also been postulated to affect post-transcriptional processing of cellular mRNAs. I have compared the abilities of NS1 gene products from different human Influenza strains to counteract the antiviral host response and found that Influenza NS1 proteins use different strategies to overcome the IFN-induced antiviral state. In harmony with the New York Influenza Center of Excellence at University of Rochester, my future work proposes to study the molecular mechanism(s) used by Influenza NS1 to overcome the antiviral state and compare the inhibition of the Type I IFN response of different viral strains. These results will be applied to generate recombinant live-attenuated Influenza viruses carrying altered NS1 proteins that can be used as putative vaccine candidates against this important biodefense agent.
- Recent Publications
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Lai C, Struckhoff JJ, Schneider J, Martinez-Sobrido L, Wolff T, García-Sastre A, Zhang DE, Lenschow DJ Mice lacking the ISG15 E1 enzyme, UbE1L, demonstrate increased susceptibility to both mouse adapted and non-adapted influenza B virus infection. J Virol. 2008 Nov 12;
Hai R, Martínez-Sobrido L, Fraser KA, Ayllon J, García-Sastre A, Palese P Influenza B NS1 Truncation Mutant Viruses: A Live-attenuated Vaccine Approach. J Virol. 2008 Sep 3; - Muñoz-Fontela C, Macip S, Martínez-Sobrido L, Brown L, Ashour J, García-Sastre A, Lee SW, Aaronson SA Transcriptional role of p53 in interferon-mediated antiviral immunity. J Exp Med. 2008 Jul 28;
- Basler, C. F., A. Mikulasova, L. Martinez-Sobrido, J. Paragas, E. Muhlberger, M. Bray, H. D. Klenk, P. Palese, and A. Garcia-Sastre. 2003. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3.
- Cardenas, W. B., Y. M. Loo, M. Gale, Jr., A. L. Hartman, C. R. Kimberlin, L. Martinez-Sobrido, E. O. Saphire, and C. F. Basler. 2006. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J Virol 80:5168-78.
- Garcia-Barreno, B., J. Steel, M. Paya, L. Martinez-Sobrido, T. Delgado, R. P. Yeo, and J. A. Melero. 2005. Epitope mapping of human respiratory syncytial virus 22K transcription antitermination factor: role of N-terminal sequences in protein folding. J Gen Virol 86:1103-7.
- Grimm, D., P. Staeheli, M. Hufbauer, I. Koerner, L. Martinez-Sobrido, A. Solorzano, A. Garcia-Sastre, O. Haller, and G. Kochs. 2007. Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. Proc Natl Acad Sci U S A 104:6806-11.
- He, Q., L. Martinez-Sobrido, F. O. Eko, P. Palese, A. Garcia-Sastre, D. Lyn, D. Okenu, C. Bandea, G. A. Ananaba, C. M. Black, and J. U. Igietseme. 2007. Live-attenuated influenza viruses as delivery vectors for Chlamydia vaccines. Immunology 122:28-37.
- Igietseme, J. U., He, Q. ,Elko, F. O., Martínez-Sobrido, L., Palese, P., García-Sastre, A. ,and Black, C.M. 2005. Development of vaccines to prevent chlamydial STDs. Mucosal Immunolgy update 13:11-16.
- Jennings, S., L. Martinez-Sobrido, A. Garcia-Sastre, F. Weber, and G. Kochs. 2005. Thogoto virus ML protein suppresses IRF3 function. Virology 331:63-72.
- Kochs, G., A. Garcia-Sastre, and L. Martinez-Sobrido. 2007. Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol 81:7011-21.
- Kopecky-Bromberg, S. A., L. Martinez-Sobrido, M. Frieman, R. A. Baric, and P. Palese. 2007. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol 81:548-57.
- Kopecky-Bromberg, S. A., L. Martinez-Sobrido, and P. Palese. 2006. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J Virol 80:785-93.
- Loo, Y. M., J. Fornek, N. Crochet, G. Bajwa, O. Perwitasari, L. Martinez-Sobrido, S. Akira, M. A. Gill, A. Garcia-Sastre, M. G. Katze, and M. Gale, Jr. 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82:335-45.
- Martinez-Sobrido, L., and A. Garcia-Sastre. 2007. Recombinant influenza virus vectors. Future Virology 2:401-416.
- Martinez-Sobrido, L., and A. Garcia-Sastre. 2006. Virus complementation assays to identify interferon antagonists. Viral Immunity. Methods and Protocols. Humana Press Inc.
- Martinez-Sobrido, L., P. Giannakas, B. Cubitt, A. Garcia-Sastre, and J. C. de la Torre. 2007. Differential inhibition of type I interferon induction by arenavirus nucleoproteins. J Virol 81:12696-703.
- Martinez-Sobrido, L., N. Gitiban, A. Fernandez-Sesma, J. Cros, S. E. Mertz, N. A. Jewell, S. Hammond, E. Flano, R. K. Durbin, A. Garcia-Sastre, and J. E. Durbin. 2006. Protection against respiratory syncytial virus by a recombinant Newcastle disease virus vector. J Virol 80:1130-9.
- Martinez-Sobrido, L., E. I. Zuniga, D. Rosario, A. Garcia-Sastre, and J. C. de la Torre. 2006. Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus. J Virol 80:9192-9.
- Mayer, D., K. Molawi, L. Martinez-Sobrido, A. Ghanem, S. Thomas, S. Baginsky, J. Grossmann, A. Garcia-Sastre, and M. Schwemmle. 2007. Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches. J Proteome Res 6:672-82.
- Mibayashi, M., L. Martinez-Sobrido, Y. M. Loo, W. B. Cardenas, M. Gale, Jr., and A. Garcia-Sastre. 2007. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 81:514-24.
- Munoz-Jordan, J. L., M. Laurent-Rolle, J. Ashour, L. Martinez-Sobrido, M. Ashok, W. I. Lipkin, and A. Garcia-Sastre. 2005. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol 79:8004-13.
- Schickli, J. H., A. Flandorfer, T. Nakaya, L. Martinez-Sobrido, A. Garcia-Sastre, and P. Palese. 2001. Plasmid-only rescue of influenza A virus vaccine candidates. Philos Trans R Soc Lond B Biol Sci 356:1965-73.
- Spiegel, M., A. Pichlmair, L. Martinez-Sobrido, J. Cros, A. Garcia-Sastre, O. Haller, and F. Weber. 2005. Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. J Virol 79:2079-86.
- Stertz, S., M. Reichelt, M. Spiegel, T. Kuri, L. Martinez-Sobrido, A. Garcia-Sastre, F. Weber, and G. Kochs. 2007. The intracellular sites of early replication and budding of SARS-coronavirus. Virology 361:304-15.
- Vecino, W. H., N. M. Quanquin, L. Martinez-Sobrido, A. Fernandez-Sesma, A. Garcia-Sastre, W. R. Jacobs, Jr., and G. J. Fennelly. 2004. Mucosal immunization with attenuated Shigella flexneri harboring an influenza hemagglutinin DNA vaccine protects mice against a lethal influenza challenge. Virology 325:192-9.
- Vigil, A., M. S. Park, O. Martinez, M. A. Chua, S. Xiao, J. F. Cros, L. Martinez-Sobrido, S. L. Woo, and A. Garcia-Sastre. 2007. Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus. Cancer Res 67:8285-92.