Salmonella enterica causes significant disease in humans and animals. Like many gram-negative pathogens utilizes its flagellar organelles for motility. Flagellar motility is essential for Salmonella virulence and the establishment of biofilms. Assembly of the flagellum requires a specialized secretion apparatus, which is a member of family of secretion systems, termed type III secretion (T3S) systems that are used by plant and animal pathogens to secrete virulence determinants into host cells. The flagellar T3S system exports proteins from the cytoplasm into a central channel of the flagellar structure during the assembly process. Proteins polymerize into place at the tip of the elongating structure. This proposal will support research designed to characterize the flagellar assembly process and determine the mechanisms used by the flagellar T3S system that selects specific substrates and what determines how substrates are ordered for secretion with respect to each other. This proposal specifically addresses the mechanisms of secretion substrate selection, the type III secretion-specificity switch mediated by FliK, the flagellar rod assembly, and the formation of the PL-ring outer membrane pore that couples rod completion to hook growth initiation. In addition, the coupling of flagellar gene expression to the global regulatory pathways at the flagellar master control operon, flhDC, will be analyzed. In addition the mechanisms by which the numerous regulators we recently discovered control flhDC both at the level of operon transcription and post-transcriptional control. Regulators of flagellar gene expression include H- NS, CrsA, PhoPQ, DnaK, cAMP-CAP, LhrA, RtsB, SlyA FimZ, PefI-SrgD, RcsB, OmpR, EcnR, FliT and YdiV. Research will focus on the coupling of flhDC expression with SpiI virulence gene expression through the recently discovered FliZ-HilD-EcnR pathway, and the putative cyclic di-GMP phosphodiesterase protein YdiV.

Public Health Relevance

Salmonella enterica causes significant disease in humans and animals. Like many gram-negative pathogens utilizes its flagellar organelles for motility and pathogenesis. Both motility- and virulence-associated type III secretion systems play important roles in the infection process and their characterization provides numerous potential drug targets for development of therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056141-16
Application #
8520316
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Flicker, Paula F
Project Start
1998-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
16
Fiscal Year
2013
Total Cost
$394,534
Indirect Cost
$132,175
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Guo, Shukui; Alshamy, Israa; Hughes, Kelly T et al. (2014) Analysis of factors that affect FlgM-dependent type III secretion for protein purification with Salmonella enterica serovar Typhimurium. J Bacteriol 196:2333-47
Mouslim, Chakib; Hughes, Kelly T (2014) The effect of cell growth phase on the regulatory cross-talk between flagellar and Spi1 virulence gene expression. PLoS Pathog 10:e1003987
Galeva, Anna; Moroz, Natalia; Yoon, Young-Ho et al. (2014) Bacterial flagellin-specific chaperone FliS interacts with anti-sigma factor FlgM. J Bacteriol 196:1215-21
Chevance, Fabienne F V; Le Guyon, Soazig; Hughes, Kelly T (2014) The effects of codon context on in vivo translation speed. PLoS Genet 10:e1004392
Singer, Hanna M; Erhardt, Marc; Hughes, Kelly T (2014) Comparative analysis of the secretion capability of early and late flagellar type III secretion substrates. Mol Microbiol 93:505-20
Singer, Hanna M; K├╝hne, Caroline; Deditius, Julia A et al. (2014) The Salmonella Spi1 virulence regulatory protein HilD directly activates transcription of the flagellar master operon flhDC. J Bacteriol 196:1448-57
Erhardt, Marc; Mertens, Max E; Fabiani, Florian D et al. (2014) ATPase-independent type-III protein secretion in Salmonella enterica. PLoS Genet 10:e1004800
Cohen, Eli J; Hughes, Kelly T (2014) Rod-to-hook transition for extracellular flagellum assembly is catalyzed by the L-ring-dependent rod scaffold removal. J Bacteriol 196:2387-95
Erhardt, Marc; Singer, Hanna M; Wee, Daniel H et al. (2011) An infrequent molecular ruler controls flagellar hook length in Salmonella enterica. EMBO J 30:2948-61
Erhardt, Marc; Namba, Keiichi; Hughes, Kelly T (2010) Bacterial nanomachines: the flagellum and type III injectisome. Cold Spring Harb Perspect Biol 2:a000299

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