Research project There are six specialized secretion systems in Gram-negative bacteria. The Type VI secretion systems (T6SSs) are the most abundant and critical for the virulence of many important human pathogens such as Vibrio cholerae and Pseudomonas aeruginosa, and used to establish eukaryotic host infections, but also to compete with our bacteria. How these sophisticated multicomponent systems are regulated and assembled is still not fully known.
There are six specialized secretion systems in Gram-negative bacteria. The Type VI secretion systems (T6SSs) are the most abundant and critical for the virulence of many important human pathogens such as Vibrio cholerae and Pseudomonas aeruginosa, and used to establish eukaryotic host infections, but also to compete with our bacteria. How these sophisticated multicomponent systems are regulated and assembled is still not fully known.
While most systems share a common set of so-called core components, several of these are lacking in the T6SS of Francisella tularensis. This highly virulent pathogen causes tularemia in humans and many animal species, and depend on its T6SS to invade and replicate within the host cell cytosol. With regard to Ft T6SS regulation, we have recently identified a critical and unique role of the ClpB chaperone. The prototypical role is due to its disaggregation activity, an essential mechanism for survival during heat shock. We identified key residues for this activity by molecular dynamic simulation and by targeted mutagenesis demonstrated that the disaggregation activity was dispensable for T6S, intracellular replication, and virulence in a mouse model. The latter functions were all related to the integrity of the N-terminal of ClpB. The findings illustrate a novel function of ClpB independent of its prototypical function related to the handling of cellular stress. The work was published in PLoS Pathogens in April, 2020.
We will also elucidate the composition and assembly of the F. tulrarensis T6SS baseplate, the structure that connects the membrane complex with the syringe like tail complex, predicted to deliver toxins into host cells. By in silico analyses and hands-on experiments, we have identified certain components of the baseplate and will now identify the other components by a similar approach. The molecular details of these interactions within the model organism Francisella novicida as well as in the human pathogenic subspecies, holarctica and tularensis, will be further investigated.
