Infectious Diseases: Shigellosis

• Shankar Thangamani
• Sangun Lee
• Gillian Beamer
• Charles Shoemaker
• Saul Tzipori

Shigellosis is a major cause of diarrhea and dysentery with high morbidity and mortality in many parts of the world. Since Shigella species are primarily pathogens of humans and some primates, studies on pathogenesis, vaccine reactogenicity and immunogenicity are mostly determined directly in human volunteers. The lack of animal models has been a major obstacle in the development of effective therapy and prevention. Researchers at the Department of Infectious Disease and Global Health are developing and evaluating the gnotobiotic piglet as a model for shigellosis. Several drawbacks for using non-human primates as a model include expense and the high ID50 required to induce infection and disease which is some six logs higher than that required for humans. The objective of this work is to develop a well-characterized reproducible animal model, and identify disease parameters that are shared with shigellosis in humans and those that are unique to the model. We have also begun development of Anti-infective VNAs consisting of single-domain antibodies (sdAbs) derived from alpacas, called VHHs, that neutralize Shigella infectivity through binding to virulence factors. The strategy is closely related to the antitoxin strategy described at the Novel Antitoxin Agents webpage. A recent project was begun in collaboration with Dr Eileen Barry, University of Maryland, who is developing vaccine candidates against E. coli O157, ETEC and Shigellosis. This project is part of the NIH funded Program, namely the Enteric Center of Excellence in Translational Research (E-CETR). These candidate vaccines are being evaluated for safety and immunogenicity in the gnotobiotic piglet model of acute diarrhea.

Publications

• Jeong KI, Venkatesan MM, Barnoy S, Tzipori S.. 2013. Evaluation of virulent and live Shigella sonnei vaccine candidates in a gnotobiotic piglet model. Vaccine. 31:4039-46
• Kuntumalla S, Zhang Q, Braisted JC, Fleischmann RD, Peterson SN, Donohue-Rolfe A, Tzipori S, Pieper R. 2011. In vivo versus in vitro protein abundance analysis of Shigella dysenteriae type 1 reveals changes in the expression of proteins involved in virulence, stress and energy metabolism. BMC Microbiol. 1186/1471-2180-11-147.
• Jeong KI, Zhang Q, Nunnari J, Tzipori S. 2010. A piglet model of acute gastroenteritis induced by Shigella dysenteriae Type 1. J Infect Dis. 201:903-11.
• Barnoy S, Jeong KI, Helm RF, Suvarnapunya AE, Ranallo RT, Tzipori S, Venkatesan MM. 2010. Characterization of WRSs2 and WRSs3, new second-generation virG(icsA)-based Shigella sonnei vaccine candidates with the potential for reduced reactogenicity. Vaccine. 28:1642-54.
• Pieper R, Zhang Q, Parmar PP, Huang ST, Clark DJ, Alami H, Donohue-Rolfe A, Fleischmann RD, Peterson SN, Tzipori S. 2009. The Shigella dysenteriae serotype 1 proteome, profiled in the host intestinal environment, reveals major metabolic modifications and increased expression of invasive proteins. Proteomics. 9:5029-45.
• Kuntumalla S, Braisted JC, Huang ST, Parmar PP, Clark DJ, Alami H, Zhang Q, Donohue-Rolfe A, Tzipori S, Fleischmann RD, Peterson SN, Pieper R. 2009. Comparison of two label-free global quantitation methods, APEX and 2D gel electrophoresis, applied to the Shigella dysenteriae proteome. Proteome Sci. 7:22.