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Molecular mechanisms of bacterial motility and type-III secretion in virulence of Salmonella

Final Report Summary - SALMOVIR (Molecular mechanisms of bacterial motility and type-III secretion in virulence of Salmonella)

The incidence of foodborne outbreaks caused by Enterobacteriaceae, including Salmonella enterica, remains substantial and constitutes a significant socioeconomic burden in Europe and worldwide.
Salmonella enterica are motile, intracellular pathogens that employ multiple virulence fac- tors, including flagella and needle-like injectisome devices, to efficiently colonize the host. The flagellum and injectisome are complex self-assembling nanomachines and their function relies on protein export via a conserved type III secretion system. However, the molecular details of protein secretion via the type III export apparatus remains largely obscure. In addition, complex regulatory mechanisms control the biosynthesis of the flagellum and virulence-related injectisome and substantial transcriptional cross talk between the various virulence factors exists that is poorly understood.

The aim of this project is to decipher the molecular mechanisms of important virulence traits of Salmonella with a focus on bacterial motility and the molecular mechanism of type-III protein secretion. The long-term goal of the research program is to exploit the gained knowledge of the molecular function of conserved virulence factors for the development of novel antimicrobial therapies targeted against these virulence traits.

Here, we analysed the self-assembly mechanisms of the bacterial flagellum and contribution of motility to Salmonella virulence. We determined the growth rate of individual flagella in real-time and developed a biophysical model that explains how flagella grow outside the cell in the absence of any conventional energy source. We further uncovered a novel flagellin phase-dependent swimming behavior on cell surfaces, which greatly affects host cell invasion and virulence in the mouse model.
We further characterized gene regulatory networks involved in flagella production and found that a novel, flagellar-dependent factor, RflM, mediates specificity of the global 2-component response regulator RcsB in regulation of flagellar synthesis. Finally, we aim to elucidate the assembly mechanisms and molecular function of bacterial type-III secretion systems (T3SS). We identified critical charged residues in a integral membrane protein that is thought to be a main component of the proton-driven protein export function of the T3SS. We further found that the flagella-specific integral membrane protein functions as a chaperone to facilitate T3SS core complex formation during assembly of the bacterial flagellum.