Jeffrey Withey, Ph.D., is an Associate Professor in the Department of Immunology and Microbiology. Dr. Withey earned his Ph.D. in Cellular and Molecular Biology at the University of Michigan in 2000. His postdoctoral studies were in the laboratories of Drs. David Friedman and Victor DiRita at the University of Michigan. Dr. Withey joined our faculty in 2006.
Dr. Withey has worked at the National Institute for Cholera and Enteric Diseases (NICED) in Kolkata, India as part of his effort to develop an animal model for cholera. In addition, he is on the editorial boards of Infection and Immunity, Journal of Bacteriology, Journal of Microbiological Methods, and Current Clinical Microbiology Reports.
The Withey lab studies bacterial pathogenesis with an emphasis on the regulation of virulence gene expression. Our current model system is Vibrio cholerae, the causative agent of the severe diarrheal disease cholera. V. cholerae is an aquatic bacterium that causes disease when ingested by humans in contaminated water. After ingestion, V. cholerae alters gene expression to produce virulence factors that result in disease. The two major virulence factors of V. cholerae in humans are the cholera toxin (CT) and the toxin co-regulated pilus (TCP). A complex network of transcription regulators controls expression of the genes involved in virulence, including those that encode CT and TCP, together with a collection of other genes whose exact roles in pathogenesis are unclear. The direct transcriptional activator of the majority of these virulence genes is ToxT protein, which is a member of the large AraC/XylS family of transcription regulators. A major focus of the lab in the past several years has been the identification of in vivo signals that control virulence gene expression by affecting ToxT activity. Now that some of these signals have been identified, we are determining the precise mechanisms by which they alter gene expression, resulting in human disease.
Another major research focus is the development of zebrafish as a natural animal model for V. cholerae. In collaboration with Dr. Melody Neely, we successfully established the viability of this model. V. cholerae colonize the zebrafish intestinal tract simply by exposure in water, resulting in diarrhea and signs of pathogenesis in the fish. Infected fish can then transmit the disease to naïve fish. Thus this model in a natural V. cholerae host recapitulates the infectious cycle in humans. Current work is aimed at identifying colonization factors that are required for V. cholerae to survive in the fish and further characterizing bacterial pathogenesis using this new model.
- Howlader, D.R., Sinha, R., Nag, D., Majumder, N., Mukherjee, P., Bhaumik, U., Withey, J.H., and Koley, H. “Zebrafish as a novel model for Non-Typhoidal Salmonella pathogenesis, transmission and vaccine efficacy.” Vaccine, 34:5099-5106 (2016)
- Nag, D., Sinha, R., Mukherjee, P., Withey, J.H., and Koley, H. “Immunization of mice with a live transconjugant Shigella hybrid strain induced Th1 and Th17 cell mediated immune responses and confirmed passive protection against heterologous shigellae.” Scandinavian Journal of Immunology, 83(2):92-101 (2016)
- Withey, J.H., Nag, D., Plecha, S.C., Sinha, R., and Koley, H. “Conjugated linoleic acid reduces cholera toxin production in vitro and in vivo by inhibiting Vibrio cholerae ToxT activity,” Antimicrobial Agents And Chemotherapy, 59(12):7471-7576 (2015)
- Plecha, S.C. and Withey, J.H. “[14C] linoleic Acid Uptake and Fractionation Assay in Vibrio cholerae.” Bio-protocol 5(24): e1682 (2015)
- Nag, D., Sinha, R., Mukherjee, P., Withey, J.H., and Koley, H. “Immunization of mice with a live transconjugant Shigella hybrid strain induced Th1 and Th17 cell mediated immune responses and confirmed passive protection against heterologous shigellae.” Scandinavian Journal of Immunology, In Press (2015)
- Plecha, S.C., and Withey, J.H. “The mechanism for inhibition of Vibrio cholerae ToxT activity by the unsaturated fatty acid components of bile.” Journal of Bacteriology, 197(10):1716-1725 (2015)
- Thomson, J.J., Plecha, S.C., and Withey, J.H. “A small unstructured region in Vibrio cholerae ToxT mediates the response to positive and negative effectors and ToxT proteolysis.” Journal of Bacteriology 197(3):654-668 (2015)
- Park, B., Zielke, R., Wierzbicki, I., Mitchell, K.C., Withey, J.H., and Sikora, A. "A new metalloprotease secreted by the Type II Secretion System links Vibrio cholerae with collagen." Journal of Bacteriology, 197:1051-1064 (2015)
- Rowe, H.M. Withey, J.H., and Neely, M.N. “Zebrafish as a model for zoonotic aquatic pathogens.” Developmental and Comparative Immunology, 46(1):96-107(2014)
- Thomson, J.J., and Withey, J.H. “Bicarbonate increases binding affinity of Vibrio cholerae ToxT to virulence gene promoters.” Journal of Bacteriology, 196(22):3872-3880 (2014)
- Runft, D., Mitchell, K.C., Abuaita, B.H., Allen, J., Bajer, S., Ginsberg, K, Neely, M.N., and Withey, J.H. “Zebrafish as a Natural Host Model for Vibrio cholerae Colonization and Transmission.” Applied and Environmental Microbiology, 80(5):1710-1717. (2014)