Activation and regulation of the T3SS during infection

Bacteria need to make sure that the right amount of the correct effector proteins is translocated into a target cell without alerting the host immune system. Therefore, substrate specificity and translocation rate of the injectisome must be tightly controlled, in acute as well as in persistent infections.

The activity of the T3SS thus needs to be regulated; however, little is known about how environmental signals regulate the function of the T3SS. Our lab has recently discovered that T3SS composition and function quickly and strongly respond to changes in the external conditions, which provides a striking example for the functional regulation of the T3SS by the environment. We now want to identify the regulatory pathways involved in this regulation, and especially the events at the injectisome itself.

To better understand how different bacteria use the T3SS, we compare its function and regulation in Yersinia enterocolitica and Pseudomonas aeruginosa. Applying our experience in live microscopy to the P. aeruginosa T3SS allows us to build on the wealth of studies that have described its regulatory networks, and to determine the link between the signaling pathways and the T3SS. Regulation of the T3SS in P. aeruginosa is directly relevant for the outcome of nosocomial infections, and hence a better understanding is a key step towards preventing healthcare-related infections. Comparing the regulation of the Y. enterocolitica and P. aeruginosa T3SS, we can discern general and species-specific mechanisms in the regulation of type III secretion, a crucial prerequisite for the development of generic T3SS inhibitors.

The T3SS is functionally regulated on different layers. (A) The activity of the T3SS is influenced by various external cues (indicated by vertical arrows), including host cell contact, the level of previously injected effectors, and the local pH and oxygen concentration. Additional signals and the pathways that integrate these signals and relay them to the T3SS are currently unknown (indicated by red X). External signals that can control or inhibit the T3SS are indicated by the green Y. (B/C) Both the localization of EGFP-labeled T3SS components (fluorescence micrographs in B) and the clustering and distribution of injectisomes (marked in red in cryo-electron tomograms in C) are directly influenced by external conditions. Adapted from Diepold et al., 2015, Kudryashev et al., 2015, and Diepold et al., 2017. The T3SS is functionally regulated on different levels. (A) The activity of the T3SS is influenced by various external cues (indicated by vertical arrows), including host cell contact, the level of previously injected effectors, and the local pH and oxygen concentration. Additional signals and the pathways that integrate these signals and relay them to the T3SS are currently unknown (indicated by red X). (B/C) Both the localization of EGFP-labeled T3SS components (fluorescence micrographs in B) and the clustering and distribution of injectisomes (marked in red in cryo-electron tomograms in C) are directly influenced by external conditions. Adapted from Diepold et al., 2015, Kudryashev et al., 2015, and Diepold et al., 2017.
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