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Xuming Zhang
Professor, Department of Microbiology & Immunology Virology Research Interest: Molecular biology and pathogenesis of Coronaviruses Ph.D ., Justus-Liebig University of Giessen, Giessen, Germany Postdoctoral , Louisiana State University - Baton Rouge; University of Southern California School of Medicine Phone: (501) 686-7415 Research Description Coronaviruses are a group of RNA viruses that infect human and diverse species of animals, causing respiratory, gastrointestinal, neurological and immune-mediated diseases. Murine coronavirus mouse hepatitis virus (MHV) causes encephalomyelitis and demyelination of the central nervous system in rodents, which resemble the neuropathologic changes in multiple sclerosis patients. In our laboratory, we are interested in understanding the molecular basis of multiple sclerosis and other neurodegenerative diseases by using MHV as an animal model. In the recent past, we have discovered that MHV infection of rat oligodendrocytes results in apoptotic cell death, which is caspase-dependent and is mediated via the Fas signaling pathway. This finding may provide one of the potential mechanisms for the destruction of oligodendrocytes by MHV infection. We are also interested in understanding the mechanisms of viral RNA persistence in the central nervous system (CNS). In contrast to the common belief that viral genes control persistence, we have found that cellular proteins play a critical role in establishment and maintenance of viral RNA persistence in CNS cells. Over-expression of a single cellular protein Bcl-xL in the oligodendrocytes or a brief treatment with serum can rescue cells from MHV-induced apoptosis and convert acute, cytolytic infection to persistent, nonproductive infection. Using the DNA microarray technology, we found more than 200 cellular genes whose expressions are altered by MHV infection. We are currently characterizing the mechanisms and biochemical pathways by which the expression of these cellular genes is regulated by virus infection and these proteins in turn regulate viral persistence. We have also found that oligodendrocyte differentiation, dendrite growth and myelin basic protein expression are suppressed by MHV persistence. Mechanistic understanding of the consequence of viral persistence in CNS cells will be our future endeavor. We are also interested in understanding the mechanisms by which viral RNA synthesis is regulated. In our laboratory, we have identified several cis-acting RNA elements and cellular proteins, which are involved in regulation of coronaviral RNA synthesis. Recently we have found that MHV infection induces MEK/ERK MAP kinase signal transduction; chemical compounds and siRNAs block MEK/ERK activation and also inhibit viral RNA synthesis. Knockdown of a transcription factor Egr-1 by siRNA also inhibits viral production. Currently our researches focus on elucidating the biochemical mechanisms underlying the regulation of coronaviral RNA synthesis by cellular proteins. In addition, we are developing infectious cDNA clones and viral vectors that may be used for expression of viral and cellular proteins and for development of vaccines. References Yu, D., Zhu, H., Liu, Y., Cao, J., and Zhang, X.M. (2009). Regulation of proinflammatory cytokine expression in primary mouse astrocytes by coronavirus infection. J. Virol. (in press) Zhu, H., Yu, D., and Zhang, X.M. (2009). The spike protein of murine coronavirus regulates viral genome transport from cell surface to endoplasmic reticulum during infection. J. Virol. Jul 1. [Epub ahead of print] Pu, Y. and Zhang, X.M. (2008). Mouse hepatitis virus type 2 enters cells through clathrin-mediated endocytic pathway independent of Eps15. J. Virol. 82:8112-8123. Liu, Y., and Zhang, X.M. (2007). Murine coronavirus-induced oligodendrocyte apoptosis is mediated through the activation of the Fas signaling pathway. Virology 360:364-375. Cai, Y. Liu, Y. and Zhang, X.M. (2007). Suppression of coronavirus replication by inhibition of the MEK signaling pathway. J. Virol. 81:446-456. Cai, Y., Liu, Y., and Zhang, X.M. (2006). Induction of transcription factor Egr-1 gene expression in astrocytoma cells by murine coronavirus infection. Virology 355:152-163. Zhu, H., Liu, Y., Cai, Y., Yu, D., Pu. Y., Harmon, L., and Zhang, X.M. (2006). Toward the development of an infectious cDNA clone of a human enteric coronavirus. Adv. Exp. Med. Biol. 581:427-430. Yu, D. and Zhang, X.M., (2006). Differential induction of proinflammatory cytokines in primary mouse astrocytes and microglia by coronavirus infection. Adv. Exp. Med. Biol . 58:407-410 . Liu, Y., and Zhang, X.M. (2006). Persistent coronavirus infection in progenitor oligodendrocytes. Adv. Exp. Med. Biol . 581: 379-384. Liu, Y., Pu, Y., and Zhang, X.M. (2006). Role of the mitochondrial signaling pathway in murine coronavirus-induced oligodendrocyte apoptosis. J. Virol . 80:395-403. Liu, Y., and Zhang, X.M. (2005). Expression of cellular oncogene Bcl-xL prevents coronavirus-induced cell death and converts acute to persistent infection in progenitor rat oligodendrocytes. J. Virol .79 :47-56. Zhang, X.M., (2003). Mechanisms of coronavirus subgenomic RNA transcription. Pp.109-127. In : RNA viruses: Mechanisms of replication and transcription (ed.: X.M. Zhang). Research Signpost. Liu, Y., Cai, Y., and Zhang, X.M. (2003). Induction of caspase-dependent apoptosis in cultured rat oligodendrocytes by murine coronavirus is mediated during cell entry and does not require virus replication. J. Virol . 77:11952-11963. Cai, Y., Yu, D., Liu, Y., and Zhang,X.M. (2003). Down-regulation of transcription of the proapoptotic gene BNip3 in cultured astrocytes by murine coronavirus infection. Virology 316:104-115.
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