Project: Integrity of the Salmonella-containing vacuole as decisive event in host cell exit of Salmonella entericaCopyright: © M. Hensel
Salmonella enterica is an invasive intracellular pathogen causing a range of infectious diseases ranging from mild gastroenteritis to life-threatening systemic typhoid fever. Diseases by Salmonella are still frequent and typhoid fever and non-typhoidal systemic Salmonellosis are major health issues in developing countries, as are multidrug-resistant strains of Salmonella. S. enterica serovar Typhimurium (STM) serves as a model system for investigating mechanisms of pathogen-host cell interactions, and systemic infections in a murine model. S. enterica serovars Typhi (STY) and Paratyphi (SPA) are human-restricted serovars that are responsible for systemic diseases such as typhoid fever.
STM resides in a membrane-bound compartment referred to as Salmonella-containing vacuole (SCV). Work on STM revealed that the bacteria survive and proliferation within in the SCV until high bacterial densities are reached. If specific exit strategies lead to release of STM from host cells after intracellular proliferation, remains to be determined. Depending on the type of host cells, loss of SCV integrity and access to host cell cytosol has different effects that are linked to exit strategies. (i) induction of host cell death by pyroptosis, (ii) hyper-replication in host cell cytosol and cell damage, or (iii) expulsion of cells with cytosolic STM from epithelial layers.
One thematic area addressed in SPP 2225 is the exit from vacuolar compartment as a prerequisite of host cell exit. This project will investigate mechanisms of control and disintegration of the SCV in S. enterica-infected cell. Depending on the type of host cell, this event could result in exit events in the focus of SPP 2225, i.e. the initiation of programmed cell death or the active lytic destruction of the host cell.
The project will investigate the role of SCV integrity and cytosolic access as requirements for subsequent exit from host cells. Based on observations in the field and own research, hypotheses were set up to be tested in the proposed project. Specific aims are:
To provide improved experimental tools and models for analyses of Salmonella exit event, the project aims at:
- Generation of tools for experimental control of SCV damage under defined experimental conditions
- Improving infection models for investigation of SCV integrity and exit
As analytical parts, the project will perform:
- Analyses host cell damages caused by intracellular Salmonella
- How is SCV damage mediated and how do SCV appear in the moment of rupture?
The project will further address hypothesis-driven project parts to answer:
- Are T3SS translocons inducing SCV damage, leading to exit?
- Are specific T3SS effector proteins controlling SCV integrity and rupture?