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.
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. !
| Wozniak, Christopher E; Lin, Zhenjian; Schmidt, Eric W et al. (2018) Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene. Antimicrob Agents Chemother 62: |
| Cohen, Eli J; Ferreira, Josie L; Ladinsky, Mark S et al. (2017) Nanoscale-length control of the flagellar driveshaft requires hitting the tethered outer membrane. Science 356:197-200 |
| Paradis, Guillaume; Chevance, Fabienne F V; Liou, Willisa et al. (2017) Variability in bacterial flagella re-growth patterns after breakage. Sci Rep 7:1282 |
| Tu, Jiagang; Park, Taehyun; Morado, Dustin R et al. (2017) Dual host specificity of phage SP6 is facilitated by tailspike rotation. Virology 507:206-215 |
| Erhardt, Marc; Wheatley, Paige; Kim, Eun A et al. (2017) Mechanism of type-III protein secretion: Regulation of FlhA conformation by a functionally critical charged-residue cluster. Mol Microbiol 104:234-249 |
| Chevance, Fabienne F V; Hughes, Kelly T (2017) Case for the genetic code as a triplet of triplets. Proc Natl Acad Sci U S A 114:4745-4750 |
| Hughes, Kelly T (2016) Mg2+-dependent translational speed bump acts to regulate gene transcription. Proc Natl Acad Sci U S A 113:14881-14883 |
| Wee, Daniel H; Hughes, Kelly T (2015) Molecular ruler determines needle length for the Salmonella Spi-1 injectisome. Proc Natl Acad Sci U S A 112:4098-103 |
| Hendrix, Roger W; Ko, Ching-Chung; Jacobs-Sera, Deborah et al. (2015) Genome Sequence of Salmonella Phage ?. Genome Announc 3: |
| 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 |
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