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Medical Microbiology and Immunology

Medical Microbiology and Immunology

R. Mark Wooten, Ph.D. R. Travis Taylor, Ph.D. Early Immune Responses to Bacterial Flavivirus Innate Immunity Mission Statement Our bodies possess a number of surfaces (e.g., and ) that My research is focused on the -borne members of the Fla- form essential barriers to prevent microbial invasion into deeper viviridae family, including West Nile , dengue virus and tick- tissues. Microbes that traverse these initial barriers will immediately borne encephalitis virus. Flaviviruses are significant patho- contact innate immune cells (e.g., macrophages, dendritic cells, and Infectious pathogens still remain a major of gens and we currently have limited treatment options. By evaluating Langerhans cells) that reside in these peripheral tissues, and play an interactions of virus and cellular proteins, Dr. Taylor has identified important role in initially recognizing these infectious agents and human , whereas defective or excessive key proteins that are important to antiviral responses. Under- directing an appropriate immune response. Thus, these early immunity causes an array of many other disorders standing the molecular mechanism of host responses, as well as interactions between resident immune cells and invading microbes including , autoimmune , and Medical strategies employed by to evade them, is crucial to future represent a critical juncture in deciding whether the infectious agents work in the lab aimed at developing new and effective flavivirus- will be cleared by the immune responses or will establish a persistent allergic disease. The Department of Medical specific . and disease development. Our lab is interested in and at the University identifying the mechanisms by which two different bacterial of Toledo is dedicated to the fight against these Microbiology pathogens are able to evade these early immune responses, so that they might be targeted for curative treatments. Borrelia burgdorferi is a common disorders. spirochetal bacterium that is spread by tick-bite and causes Lyme disease throughout the U.S., Europe and Asia; Lyme disease is the Microbiology explores the relationships between and most prevalent anthropod-transmitted illness in these regions of the world. Burkholderia pseudomallei is a resilient soil-dwelling bacterium microbial pathogens and their human hosts, and that is mainly found in tropical regions of the world and causes immunology studies the nature of host defense melioidosis. B. pseudomallei is designated as a Tier 1 select agent, in system against environmental insults. The Immunology that it is extremely deadly when aerosolized, and can easily be used as a biological weapon. Our work has been published in the Journal of Department contributes to the research mission Immunology, Infection and Immunity, and the Journal of Clinical Investigation. of the University by advancing basic and translational research with the ultimate goal of developing innovative and therapeutics Viviana Ferreira, D.V.M., Ph.D. Randall G. Worth, Ph.D. for infectious diseases, cancer, and inflammatory Role of Complement Regulatory Proteins in and Autoimmune Diseases disorders caused by immune dysregulation. Disease Cutting-edge technologies in biomedical Faculty are provided through the Core Our research program is directed at understanding the immune Lab; Bioinformatics, Genomics/Proteomics Core Research The complement system uses a complex set of complement regulato- of platelets in both protection from pathogenic infection Lab, and BSL-3 Lab housed in the Department. ry proteins that are either membrane-bound or in the fluid phase of and platelets as a causative or compounding factor in autoimmune plasma. Factor H is a soluble complement regulatory molecule with disease. In addition to their essential role in clot formation, platelets The Department also contributes to the teaching an essential role in the control of complement activation in plasma express many properties similar to white blood cells. We have found mission of the University by educating medical Interests and on cell surfaces. Factor H polymorphisms and have that platelets can recognize coating and lead to been linked to human diseases that often lead to severe complement- killing of the bacteria. Interestingly, platelets from with the and graduate students in basic principles of mediated damage such as atypical hemolytic uremic , , Systemic Erythematosus (SLE) have immunology, bacteriology, , and host- age-related macular degeneration, and membranoproliferative glo- antibodies bound to them which causes the platelets to become interaction. Moreover, the Department merulonephritis. We have shown factor H is essential for the protec- hypersensitive and may lead to these patients being at high of tion of cell surfaces using normal and paroxysmal nocturnal hemo- and myocardial . We study platelets from the blood contributes to the service mission of the globinuric human red blood cells as models. My research on factor H of healthy volunteers and patients with autoimmune diseases to University by providing advanced expertise in focuses on understanding the molecular mechanisms of how factor determine differences in platelet function and characteristic features microbiology and immunology and by promoting H contributes to the protection of different cell surfaces from com- of platelet responsiveness. We have also developed animal models in plement-mediated damage, and identifying how mutations in factor which platelet numbers can be modulated in order to study the role regional, state, national and international research H its ability to protect cell surfaces. Another line of research of platelets in many disease states. Our studies have revealed various programs concerning infectious diseases, focuses on properdin, the only positive regulatory protein of the therapeutic targets that may be helpful in treating patients with complement system. We and others have recently identified proper- autoimmune diseases and clotting disorders. These studies have been inflammatory disorders, and graft rejection. din as a pattern recognition molecule of the alternative pathway of published in the American Journal of , Journal of Thrombosis and complement and we are studying the molecular mechanisms in- Haemostasis, and Journal of Immunology. volved in properdin-mediated complement activation. Altogether, this research will contribute to elucidating the role of complement regulatory proteins in the prevention or of inflammato- ry diseases where complement-mediated tissue damage in known to play important roles. This research has been funded by the NIH and American Heart Association. and Immunology

Saurabh Chattopadhyay, Ph.D. Jyl Matson, Ph.D. Stanislaw M. Stepkowski, D.V.M., Ph.D., D.Sc. Innate antiviral responses, Vibrio cholerae response mechanisms and Transplantation of Organs and pathogenesis Faculty Highlights & Achievements

My research is focused on inducing of long-term allograft survival  Well-funded department with over $2.4 million sup- Our laboratory is interested in studying the host responses against We research the mechanisms by which bacteria sense and respond to (transplantation tolerance) and development of new virus in cells and mice. Innate immune responses, their extracellular environment. Vibrio cholerae is the bacterium that immunosuppressive modalities. Activation of T lymphocytes requires porting strong research projects in both basic and activated very early during virus infection, are critical for causes , a disease that continues to spread in areas of three signals, with signal 3 (delivered by cytokines) regulating cell inhibition of virus replication. The interferon system is the world where people lack access to clean drinking water. Due to proliferation, differentiation, and survival/. Cytokines binding to translational research in a collegial atmosphere, with recognized as a major antiviral innate immune response increasing resistance among V. cholerae strains, there is a need their receptors engage two molecular families, namely, Janus tyrosine approximately 20 publications each year mechanism against a broad range of viruses. We are investigating to develop additional therapeutic agents for cholera treatment. Current kinases (Jaks) and signal transducers and activators of transcription how a key transcription factor IRF3 and the induced genes (ISGs) projects in the Matson lab include identification and characterization of (Stats). Among these signaling molecules, Jak3, Stat5 and Stat3 are mount antiviral protection. Using both RNA (e.g. small molecule inhibitors of a V. cholerae stress response pathway that investigated as potential targets for selective inhibition versus  Strong record of successful faculty recruitment, reten- Paramyxoviruses) and DNA (e.g. Herpesviruses) viruses, which may be developed into cholera therapeutics. Additional studies aim to promotion of T regulatory cells and immature dendritic cells to are the important human pathogens, we are interested to uncover characterize transcriptional responses of V. cholerae to various stresses to produce transplantation tolerance. Novel tyrosine (Y) phosphory- tion, and timely promotions with tenure novel host response mechanisms to protect against them. determine pathways associated with bacterial fitness and pathogenesis. lation sites (Y905 and Y935) are investigating on Jak3 and their role in Identification of new antiviral strategies will lead to the T cell function. Similarly, Stat3 and Stat5 are investigated for development of successful therapeutic applications. differentiation of T cells into T helper 17 and T regulatory cells.  Medical student performance consistently above the Selective inhibitors of these molecules are being searched to promote national average on Step 1 USMLE Exam in sections of T effector cells versus expansion of T regulatory cells. My research is supported by NIH grant and Novartis and Icagen of microbiology, immunology, and immune systems funds. The work has been published in the Journal of Immunology, Blood, and Transplantation.  Highly successful graduate program with students earning major awards and fellowships, timely gradua- Jason F. Huntley, Ph.D. Z. Kevin Pan, M.D., Ph.D. Robert M. Blumenthal, Ph.D. tion, and establishing careers in science and industry Host-pathogen Interactions Molecular Mechanisms of Host-pathogen Interactions Evolution of Bacterial Regulation, Gene Exchange, and Pathogenesis  Outstanding service record with the university, Tole- do and surrounding communities, and in the scien- Dr. Huntley’s laboratory primarily studies Francisella tularensis, the Tumor factor alpha (TNFα) is considered one of the key Our laboratory has four areas of interest. One focuses on how gene tific community (nationally and internationally) causative agent of the zoonotic disease tularemia. F. tularensis is inflammatory mediators during bacterial infection. This powerful exchange between bacteria is naturally controlled. In bacteria, the well-recognized as one of the most dangerous bacterial protein, secreted mostly by human leukocytes such as monocytes/ acquisition of genes for factors such as toxins, and for pathogens known because of its low infectious dose, ease of macrophages, acts as a host defense against bacterial infections. antibiotic resistance, depends on sharing from other bacteria. Re-  Recent Dean’s Awards selected by UT peers: aerosolization, multiple routes of infection, and ability to induce However, when TNFα levels rise too much, it can lead to inflammatory striction-modification systems appear to serve as positive and nega- severe disease and death. Dr. Huntley’s laboratory uses a multi- disorders. A wide variety of stimuli have been shown to induce the tive gatekeepers for this important gene sharing, by cutting incoming 2015 Outstanding Research–New Investigator (Huntley) disciplinary approach to: (1) study changes in F. tularensis production of TNFα, but bacteria products are considered major DNA into pieces while protecting the bacterium’s own DNA, but the 2014 Research Excellence—Sustained Category (Stepkowski) membrane proteins during mammalian and tick infections; (2) inducers during bacterial infections. To date, most research on the precise roles in gatekeeping are still unclear (unlike their better- generate F. tularensis membrane protein mutants and examine production of TNFα has been focused on understanding how TNFα is understood roles in defense against bacterial viruses). A second area 2014 Research Excellence-New Investigator (Ferreira) their virulence and in vivo; (3) characterize the function induced by a single bacterial product. We have found that production of seeks new strategies for treating protozoal infections, by targeting an 2014 Mentoring Excellence (Pan) of individual membrane proteins; (4) develop and test new TNFα occurs when leukocytes are exposed to multiple bacterial essential enzyme that produces the critical metabolite S-adenosyl-L- vaccines to prevent tularemia; and (5) define immune responses products, and our results indicate that the bacterial products regulate methionine (AdoMet). The third area examines the role of DNA 2013 Outstanding Research Award (Stepkowski) that protect against F. tularensis infection. the production of TNFα in a synergistic manner. The control of methylation mosquitoein controlling host-virus interactions in s. 2013 Teaching Excellence-Basic Science (Ferreira) inflammation is likely to be best understood on this level. This Finally, the fourth area is focused on the evolution of the small subset More recently, Dr. Huntley’s laboratory has received funding to represents an important pathogenic phenomenon occurring during of regulatory proteins in bacteria that each control hundreds of genes 2012 Distinguished University Professor (Blumenthal) study cyanobacterial blooms, cyanobacterial hepatotoxins (e.g. bacterial infection. Our experiments provide information that is both (“global” regulators). The key questions are how these proteins func- MC-LR), and is developing new methods to remove MC-LR unique and potentially important, and will significantly expand and tion, why these particular proteins became global regulators, and how from municipal drinking water. To accomplish these goals, enhance our understanding of how inflammation is induced in vivo when their role has changed in different bacteria. This work has been fund- current projects are: (1) selecting for and isolating MC-LR- multiple bacterial products are present simultaneously. ed by the National Institutes of and National Science Founda- degrading bacteria from Lake Erie; and (2) using these MC-LR- tion, and has been published in journals such as the Journal of Bacte- degrading bacteria as biofilters to remove MC-LR from drinking riology, Nucleic Acids Research, BMC Microbiology, and Proceedings water. of the National Academy of .

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