SalmoVir · Molecular mechanisms of bacterial motility and type-III secretion in virulence of Salmonella
FP7 — People (Marie Curie Actions)
- Duration
- 2013-04-01 → 2017-03-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Salmonella are motile, gram-negative, pathogens that infect eukaryotic cells. Outbreaks of salmonellosis are a great economic and health problem worldwide. Many bacteria, like Salmonella, swim through liquid environments by rotating a helical organelle, the flagellum. This sophisticated nanomachine is functionally and structurally related to virulence-associated type-III secretion systems (T3SS) of pathogenic bacteria. The ability to move is of crucial importance for Salmonella virulence and infection of eukaryotic cells. Although the importance of bacterial motility and T3S in virulence of Salmonella is established, a detailed understanding of the expression and molecular interplay between the flagellar and virulence systems during infection is missing.The aim of this research program is to study the mechanisms of bacterial motility during bacteria-host interactions and the molecular function of T3SS using an unique combination of sophisticated bacterial genetics, microscopy, biochemistry and infection biology techniques.Both flagellar motility and the process of T3S are essential for virulence and represent attractive targets for novel anti-microbial agents. Therefore, I will analyze the general importance of flagella and bacterial motility during the Salmonella infection process (Aim 1). In complementary projects, I will focus on the molecular mechanisms of bacterial T3SS like the mechanism of substrate translocation (Aim 2), and screen for compounds that inhibit T3SS (Aim 3).The proposed research program will provide novel and fundamental insights into our understanding of the molecular details of Salmonella virulence. Thereby, the initial events required for the commitment of the bacteria to invasive diseases could become clear. Importantly, this knowledge could be used to design specific inhibitors of bacterial T3SS, which might have the potential for new anti-bacterial agents that are urgently needed at a time when antibiotic resistance is increasing.
Original text from CORDIS.
Participants
- HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH · BraunschweigCoordinatorGermany
Links
Data: CORDIS, © European Union