Salmonella pathogens infect over a billion people each year worldwide resulting in 3 million deaths annually from septicemia, mostly in HIV-infected patients and 700,000 from typhoid fever (W.H.O. estimates). It is one of many gram-negative plant and animal pathogens that have evolved specialized secretion systems, termed Type III Secretion System (TTSS), to facilitate the ordered delivery of virulence effector proteins. The pathogenic TTSSs evolved from the flagellar TTSS, which ensures the efficient and ordered assembly of the bacterial flagellum. The virulence systems have maintained the ordered delivery mechanism of the TTSS to ensure that individual virulence determinants are secreted at the appropriate stage of the infection process. The flagellum has served as a well-characterized model system, to understand how regulatory mechanisms can control the assembly of large structures, and to understand how the TTSS can differentially select substrates for secretion at the appropriate stage of the infection process. We will continue a detailed investigation of the regulation of gene expression in response to assembly of the flagellum. We have previously shown that one critical regulatory mechanism involves a regulatory protein FlgM, which is held inside the cell prior to completion of the intermediate hook-basal body structure. Upon hook-basal body completion, FlgM escapes from the cell and thus can no longer act. We will determine the signals that provide the temporal order and specificity for the secretion process. Specific mechanisms to be investigated are the dual roles for Type III Secretion Chaperones (TTSC) in assembly and gene regulation, the process of localized translation of secretion substrates at the cytoplasmic base of the flagellum and the role of the membrane-anchored translation initiation factor, Flk, in this process. This includes the roles of the FlgN and FliT chaperones in coupling transcription and translation to assembly. FlgN, a TTSC for hook-filament junction proteins, serves as a translational regulator of specific transcripts in response to assembly, while FliT, a TTSC for the filament cap, inhibits transcription of HBB genes in response to assembly. Finally, we will develop the flagellar regulatory and assembly system as a model bioinformatic system complete with feedback loops for modulating gene expression in response to clues from intermediate assembly stages. This includes a characterization of the roles of the flagellar specific alternative sigma factor, sigma-28, and its antagonist (FIgM) in this process. Because the TTSS is a target for vaccine development against gram-negative pathogens, understanding the process of assembly, secretion and regulation will aid in the development of such vaccines.
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