Keiller, Route 0609
Department of Microbiology & Immunology
Centers for Biodefense and Emerging Diseases
Phone: (409) 747-0789
Fax: (409) 747-0762
|PhD | 1997 | University of Arkansas for Medical Sciences|
|MS | 1981 | Mississippi State University|
|BS | 1976 | National Chung-Hsing University, Tai-chung, Taiwan|
Host innate immunity to and the pathogenesis of emerging and re-emerging RNA viral infections (SARS, RVF, and Avian Influenza).
My primary research is focused on understanding how RNA viruses trigger the host immune responses and how animals defend against emerging and re-emerging viruses. Specifically, we study the molecular and cellular interplays whereby the innate immune responses are initiated and regulated and how an unregulated innate immunity leads to diseases and mortality. We are particularly interested in dissecting the antiviral signaling pathways by which pathologically relevant host cells mount innate immune responses to invading viruses. We are also interested in how viruses evade the host defense system. The ultimate goal of our studies is to understand and identify novel molecules of the innate immune system as targets for preventive and therapeutic intervention against RNA viral infections.
RNA virus infection is detected by the host cells through either toll-like receptor (TLR)-3 and -7/8, which are located primarily on the endosomal membrane, or the cytosolic RNA helicase proteins RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation antigen 5), which transmitting activation signals to the cytosolic adaptor TRIF, MyD88, and MAVS/IPS, respectively, that ultimately leads the activation of an array of antiviral genes, including type I interferons (IFNs), inflammatory cytokines and chemokines, and many interferon-stimulated genes (ISGs), via at least three overlapping antiviral pathways mediated by transcription factors NFκB, interferon regulatory factor-3 (IRF-3), and ATF2/cJUN intermediate signaling molecules. Among various RNA viruses, we are currently focusing on dissecting the antiviral signaling pathways induced by severe acute respiratory syndrome coronavirus (SARS-CoV, a BSL-3 pathogen), Rift Valley Fever virus (RVFV, a BSL-3+ pathogen), Junin virus (JV, a BSL-4 pathogen), Dhori virus, a tick-born Orthomyxovirus, which is a BSL-2 pathogen sharing a strikingly similar pathogenetic mechanism with avian influenza H5N1 virus in mice. To ensure the success of our studies, we adopt a two-stage strategy for the proposed studies. Specifically, we first perform in vitro studies using virally permissive and pathologically relevant human cells, including lung epithelial cells (SARS, Dhori virus), human umbilical vascular endothelial cells (HUVEC) and hepatocytes (RVF, Dhori), along with two of the most implicated classic innate immune cells, e.g., primary human macrophages and dendritic cells (RVFV and JV). Once specific signaling pathway(s) and cellular targets are identified, we will use suitable animal models for the verification purpose. In this regard, experimental infection of mice has been used successfully as animal models. Particularly, we have been using transgenic mice expressing hACE2 (human angiotensin-converting enzyme 2), the receptor for SARS-CoV, as the animal model for SARS-CoV. We also use mouse-adapted SARS-CoV, designated MA-15, to infect wild type and various strains of selected gene knockout (KO) mice, aiming at dissecting the mechanism of host innate immunity against SARS-CoV and/or immune-mediated diseases. Various state-of-art approaches involving virology, immunology, biochemistry, molecular biology, and genetics are used to establish and characterize cell lines/clones with specific gene KO or knock down (KD) (i.e., loss-of-function) or constitutive expression (i.e., gain-of-function) phenotypes, and identify the role(s) of selected genes in the host antiviral defense. We are also interested in evaluating the impact of the cellular interplays on the pathogenesis of viruses in vitro, via using two- and/or three-dimensional culture systems. Our research is currently supported in part by grants and contracts from the National Institutes of Health, and other Pharmaceutical industries.
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