Vibrio cholerae is a Gram-negative bacterial pathogen that causes the water-borne diarrheal disease Asiatic cholera. Following ingestion by a host and entry into the upper intestine, V. cholerae colonizes the human intestine and begins to export the major virulence toxin, cholera toxin (CT). The activity of CT elicits severe diarrhea in the infected person resulting in extreme dehydration, the hallmark of cholera disease.
However, CT is not the sole toxin exported by V. cholerae. In human volunteer studies it has been shown that CT-deficient strains still elicit mild to severe diarrhea, vomiting, and other symptoms of discomfort. The search for the "reactogenicity factor" has been an ongoing process in many laboratories and has led to the discovery of numerous exported proteases and a hemolysin. My lab focuses on a newly discovered toxin, the RTX toxin.
The RTX toxin of V. cholerae causes the depolymerization of cellular actin fibers, resulting in rounding of cells in culture. The toxin is multifunctional and causes rounding of cells both by introducing covalent cross-links into cellular actin and through inactivation of Rho family GTPases. In addition, the toxin undergoes auto-processing during entry into cells stimulated by the binding of host cell small molecule co-factor.
Projects within my lab utilize a combination of cell biology and biochemical approaches to further understand the mechanisms of actin cross-linking, Rho GTPase inactivation, and auto-processing. In addition, we are working with collaborators to solve the crystal structures of the individual domains responsible for each activity.
Additional projects in the lab examine the function of a related toxin from Yersinia pestis and the association of the RTX toxin with pathogenesis in animal and relevant culture models.
Publications:
Sheahan, K.-L., C.L. Cordero, and K.J.F. Satchell, (2004) Identification of a domain within the multifunctional Vibrio cholerae RTX toxin that covalently cross-links actin, Proc. Natl. Acad. Sci. U.S.A., 101:9798-9803.
Boardman, B. and K.J.F. Satchell (2004) Vibrio cholerae strains with mutations in an atypical Type I secretion apparatus accumulate RTX toxin intracellularly, J. Bacteriol, 186:8137-8143.
Haines G.K. III, B.A. Sayed, M.S. Rohrer, V. Olivier and K.J.F. Satchell (2005) Role of TLR4 in the proinflammatory response to Vibrio cholerae O1 El Tor strains deficient in production of cholera toxin and accessory toxins, Infect. Immun. 73:6157-6164.
Cordero C, D.S. Kudryashov, E. Reisler, and K.J.F. Satchell, (2006) The actin cross-linking domain of the Vibrio cholerae RTX toxin directly catalyzes the covalent cross-linking of actin, J. Biol. Chem., epub Sept 5, 2006
Satchell, K.J.F. (2003) Activation and suppression of the proinflammatory immune response by Vibrio cholerae toxins, Microbes and Infection, 5(13):1241-7.
Fullner, K.J., W.I. Lencer, and J.J. Mekalanos (2001) Vibrio cholerae-induced cellular responses of polarized T84 intestinal epithelial cells dependent on production of cholera toxin and the RTX toxin. Infect. Immun., 69:6310-6317.
Fullner, K.J., J.C. Boucher, M.A. Hanes, G.K. Haines III, B.M. Meehan, C. Walchle, P.J. Sansonetti, and J.J. Mekalanos (2002) The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model. J. Exp Med. 195:1455-1462.
Fullner, K.J. and J.J. Mekalanos (2000) In vivo covalent crosslinking of actin by the Vibrio cholerae RTX toxin, EMBO J. 19:5315-5323.
