The bacterial flagellum is essential for motility and virulence for Gram-negative pathogens. Flagellum assembly is complex and coupled to the controlled expression of more than 70 genes in the flagellar and chemotaxis regulon. It takes many cell generations to assemble a completed flagellum. For 30 years my lab has investigated mechanisms that couple flagellar gene expression to assembly and the associated type III secretion (T3S) system. T3S is the only secretion system in Biology that undergoes a secretion-substrate transition from one class of secretion-substrates to another. One focus of this grant application is to determine the mechanism of the secretion- specificity switch in flagellar and the related virulence-specific injectisome T3S systems. The research will also determine how specific proteins are selected from the thousands present in the cytoplasm and targeted for T3 secretion. We will also characterize key gaps in the understanding of how flagellar gene regulation is coupled to assembly and how the entire flagellar regulon responds to global gene regulatory systems.

Public Health Relevance

Salmonella has three Type III (T3S) systems: i) one for secretion of flagellar protein subunits and two for injectisome and associated virulence-effector proteins. T3S is arguably the most important route through which Gram-negative animal pathogens cause disease in humans. The characterization of the Salmonella flagellum assembly, T3S substrate targeting and coupled gene regulatory mechanisms will further our understanding of host-pathogen interactions, protein- secretion specificity, and nanomachine self-assembly. These complex mechanisms provide a wealth of potential antibiotic targets to inhibit T3S-associated pathogenesis. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056141-22
Application #
10052175
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Adkins, Ronald
Project Start
1998-08-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
22
Fiscal Year
2020
Total Cost
Indirect Cost
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
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