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Geographic Medicine and Infectious Diseases

Toxin-Mediated Inflammation Research Program

Overview

Our laboratory studies the role of the inflammatory response to specific bacterial and plant toxins including Shiga toxin, produced by the deadly E. coli pathogen O157:H7 and the select agent ricin. Our goals are to understand the specific pro-inflammatory signaling pathways activated by these toxins, and to assess whether targeting inflammation by the toxins can be used as a therapeutic strategy to treat and/or prevent disease by these deadly agents.

Shiga toxin

Shiga toxin producing Eshcerichia coli (STEC) is a major cause of food-borne disease and results in significant morbidity and mortality worldwide. Severe diseases caused by STEC include hemorrhagic colitis and the hemolytic uremic syndrome (HUS), which is the leading cause of kidney failure in children in the United States. Other than supportive care there are no approved therapies for HUS, and the mechanisms by which Shiga toxin promotes HUS is poorly understood.

Together with our collaborators, we have demonstrated that Shiga toxins induce inflammatory signaling at least in part through an innate pro-inflammatory signaling pathway termed the ribotoxic stress response (RSR). Our current research aims at identifying the signaling intermediaries of this pathway, and to determine whether blocking this stress response can be used as a strategy to treat and/or prevent HUS.

Ricin toxin

As with Shiga toxin, the plant toxin ricin induces the RSR. Ricin is a select agent and bioterror threat for which no specific therapies exist. Because ricin damages cells in a manner identical to that of Shiga toxin, we have been interested in applying the knowledge gained through Shiga toxin research to the development of therapies to treat ricin-mediated disease.

Additional Research

Our laboratory also studies changes in the intestinal ecosystem during disease, with the aim of understanding how changes in this ecosystem may contribute to and/or act as a prognostic indicator of disease. As the gut ecosystem is important to proper immune function and well-being, we are conducting studies to identify how probiotic organisms are able to modulate immune function.

Faculty

Dakshina Handhyala, PhD

Publications

Stone, S.M., C.M. Thorpe, A. Ahluwalia, A.B. Rogers, F. Obata, A. Vozenilek, G.L. Kolling, A.V. Kane, B.E. Magun, and D.M. Jandhyala (2012) Shiga toxin 2-induced intestinal pathology in infant rabbits is A-subunit dependent and responsive to the tyrosine kinase and potential ZAK inhibitor imatinib. Frontiers in cellular and infection microbiology. 2:135.

Wong, J., L.B. Smith, E.A. Magun, T. Engstrom, K. Kelley-Howard, D.M. Jandhyala, C.M. Thorpe, B.E. Magun, L.J. Wood (2012) Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin. Cancer biology and therapy. 14: [Epub ahead of print]

Jandhyala, D. M., B. Magun, and C. M. Thorpe. (2012) Ricin and Shiga toxins: Effects on host cell signal transduction. In N. J. Mantis (editor) Ricin and Shiga toxins: Pathogenesis, Immunity, Vaccines and Therapeutics, Chapter 3. Current Topics in Microbiology and Immunology, 357: Springer, Berlin, Heidelberg.

Jandhyala, D. M., T. J. Rogers, A. Kane, A. W. Paton, J. C. Paton, and C. M. Thorpe (2010) Shiga toxin 2 and flagellin from Shiga toxigenic Escherichia coli super-induce IL-8 through synergistic effects on host SAPKinase activation. Infection and immunity, 78:2984-96.

Wolfson J.J., D.M. Jandhyala, L.A. Gorczyca, Z. Qadeer, C.M. Thorpe, S.D. Manning, J. Hadler, J.T. Rudrik (2009) Prevalence of the Operon Encoding Subtilase Cytotoxin in Non-O157 Shiga Toxin-producing Escherichia coli Isolated from Humans in the United States, Journal of Clinical Microbiology, 47:2058-9.

Wolfson JJ, K. L. May, C. M Thorpe, D. M. Jandhyala, J. C. Paton, and A. W. Paton (2008) Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signaling pathways. Cellular Microbiology, 10:1775-86.

Jandhyala, D. M., A. Ahluwalia, T. Obrig, and C. M.  Thorpe (2008) ZAK: a MAP3Kinase that transduces Shiga toxin and ricin induced proinflammatory cytokine expression. Cellular Microbiology, 10:1468-77.

Khaitan A, D. M. Jandhyala, C. M. Thorpe, J. M. Ritchie, and A. W. Paton (2007) The operon encoding SubAB, a novel cytotoxin, is present in shiga toxin-producing Escherichia coli isolates from the United States. Journal of Clinical Microbiology, 45:1374-5.

Jandhyala, D. M., R. C. Rigden, C. Dupont, D. Crosbie-Caird, N. Lopez-Villalobos, N. Maeda, B. Giquel, and A. Murray (2006) Humoral and cellular immune responses in sheep immunised with a 22 kilodalton exported protein of Mycobacterium avium subspecies paratuberculosis, Journal of Medical Microbiology, 55:1735-40.

Jandhyala, D. M. and M. J. Benedik, and R. C. Willson (2005) Comparison of cyanide-degrading nitrilases. Applied Microbiology and Biotechnology, 68:327-35.

Sewell, B. T., M. N. Berman, P. R. Meyers, D. Jandhyala, and M. J. Benedik (2003) The Cyanide Degrading nitrilase from Pseudomonas stutzeri AK1 Is a Two-Fold Symmetric, 14-Subunit Spiral. Structure, 11:1-20.

Jandhyala, D., M. Berman, P. R. Meyers, B. T. Sewell, R. C. Willson, and  M. J. Benedik (2003) CynD, the Cyanide Dihydtratase from Bacillus pumilus: Gene Cloning and Structural Studies. Applied and Environmental Microbiology, 69:4794-4805.

Contact Us

Phone: 617-636-7001
Fax: 617-636-8525