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Regulatory Mechanisms that govern expression of Type III Secretion systems in gram-negative bacterial pathogens

In their quest for survival, microbial pathogens have evolved elaborate mechanisms to invade and exploit their mammalian hosts. In many gram-negative bacterial bacteria type III secretion systems are main stays of virulence. These syringe-like molecular machines are employed to transport arsenals of virulence factor directly into the cytoplasm of a eukaryotic host cells. Inside the host, the toxins act to suppress and evade the innate host immune response, prepare the host for invasion, and induce apoptosis. Some of the most potent pathogens utilize type III secretion systems: Yersinia pestis, enteropathogenic E.coli, Shigella flexneri, Salmonella enterica., and Pseudomonas aeruginosa to name a few. Since disruption of the type III secretion apparatus invariably leads to a significant attenuation of virulence, the structural and functional components of the secretion machinery are considered high value drug targets. Rather than targeting individual components of secretion machinery we have decided to focus our efforts on achieving a broader impact by suppressing the regulatory cascades that activate expression of multiple type III secretion-related genes.

Structural Biology of Inc Proteins in Chlamydiae pneumoniae and Chlamydiae trachomatis

Chlamydiae species are causative agents for a large variety of diseases. Host cell invasion is one of the survival strategies the microbes employ to escape detection by the host immune system. After invasion bacteria are maintained within unique vacuoles also called inclusions. Inclusion membrane proteins or Inc proteins have been implicated as critical mediators for inclusion formation and maintenance process. Inc proteins seem to be unique to the Chlamydiae species and share little sequence homology beyond a characteristic large bilobed hydrophobic region of 40–70 amino acids. Remarkably, these proteins are translocated into mammalian cells via a type III secretion apparatus. Inside the host Inc proteins are inserted into the inclusion membrane from where they interact with a variety of host factors to facilitate invasion (for a review please see: Rockey, D.D. et al. (2002) Microbes and Infection, 4, 333–340). There is limited functional and no structural information available for Inc proteins. We will initiate structural studies on a representative subset of these proteins. The structural data, in addition to potentially providing functional insights, will form the foundation for a structure-based search for potent inhibitors that leads to the disruption of the inclusion, thus allowing more efficient clearance of an infection. Our efforts will be coordinated with work on the biology of Inc proteins ongoing in several laboratories at the University of Miami Medical School.