ABSTRACT
INTRODUCTION: Gastrointestinal infections are a significant cause of diarrhea and a worldwide problem with annually one billion illnesses and 3 to 4 million deaths. Gram negative bacteria like Enteropathogenic E. coli (EPEC) in developing countries and Enterohemorrhagic E. coli (EHEC) in the developed world are responsible for the majority of acute diarrheal episodes, especially among children less than three years of age. Pathogenic E. coli are supplied with an arsenal of effector proteins to modify and neutralize specific cellular functions of the host organism. METHODS: Based on personal and extensively published results we provide a selected overview of Gram negative virulence functions with a focus on lymphostatin. RESULTS: Lymphostatin is an effector protein encoded by lifA/efa-1 (lymphocyte inhibitory factor A/ EHEC factor for adherence). lifA/efa-1 and homologous genes have been identified in EPEC, EHEC, and mouse pathogen Citrobacter rodentium, as well as various Chlamydia strains. Multiple groups have shown that in various EHEC strains lifA/efa-1 is part of a larger pathogenicity island responsible for increased virulence. Statistically, DNA Microarray analysis associated lifA/efa-1 as the single most imortant gene with diarrhea caused by EPEC. Interestingly, lifA/efa-1 encodes for two critical enzymatic activities that have been identified in other pathogenic bacteria: glucosyltransferase- in Clostridium- and protease activity in Yersinia strains. In vitro studies identified lymphostatin as an effector protein with an immunosuppressive effect on peripheral blood and gastrointestinal mucosa T lymphocytes. Further, lymphostatin regulates the barrier function of epithelial monolayer cultures: activation of small GTPase RhoA and inhibition of Cdc42 lead to disassembly of adherens junctions and tight junctions, respectively. Besides an effect on immune and epithelial barrier function, lymphostatin also functions as an adhesion factor for EPEC and EHEC, is essential for colonization of mouse and calf intestine, and regulates bacterial effector proteins. SUMMARY: Lymphostatin is a common toxin in Gram negative bacteria with multiple functions: cell adhesion, immunosuppression, disruption of epithelial barrier function, and intestinal colonization.
