SupaSteD · Suppresion of adaptive immunity by the Salmonella effector SteD
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-09-01 → 2019-08-31
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Suppresion of adaptive immunity by the Salmonella effector SteD
Efficient immune response towards intracellular bacterial pathogens (eg. Salmonella) depends on proper mode of activation of CD4+ T lymphocytes. This is mediated by antigen presenting cells such as dendritic cells (DCs). DCs trigger CD4+ T lymphocyte-dependent specific immune response by presenting foreign antigens on major histocompatibility complex class II (MHCII). Salmonella evolved a mechanism to specifically block antigen presentation by MHCII thus inhibiting onset of appropriate immune response. The aim of this project was to reach a deep characterization of the functions of the Salmonella effector SteD on host MHCII-dependent specific immunity in an attempt to prepare a new tool for wider use in clinical practice. To reach this main goal, the work was divided into the following objectives: i) characterization of the effects of SteD on T cell activation in context of host organism; ii) obtaining a detailed understanding of SteD activity on molecular level; iii) identification of proteins targeted by SteD to modulate functions of T lymphocytes; iv) development of SteD as a tool usable for controlled modulation of adaptive immunity. Results obtained throughout the project helped to uncover a function of a formerly uncharacterised human protein which is crucial for SteD activity. Interaction between SteD and this protein is a key step for inhibition of antigen presentation by MHCII and for preventing establishment of productive interaction between DCs and T lymphocytes. Therefore, T lymphocytes developing under the influence of SteD-manipulated DCs show features of regulatory T cells rather than immunostimulatory CD4+ helper T lymphocytes.
Data: CORDIS, © European Union
Project objective
In this project, I propose to characterize the influence of SteD, an effector of a globally important bacterial pathogen Salmonella enterica, on T cell development, and its potential therapeutic application. In the mouse model of S. enterica infection, the onset of the specific immune responses is delayed significantly in comparison to other bacterial pathogens. Recent work by the group of Prof. Holden, who is the supervisor of this project, a world leader in the field of Salmonella pathogenesis and the Director of the MRC Centre for Molecular Bacteriology and Infection (MRC-CMBI) at Imperial College London, identified SteD, an effector of the Type III Secretion System (T3SS) encoded by Salmonella pathogenicity island 2 (SPI-2), as the first example of a virulence factor that reduces surface-localised mature Major Histocompatibility Complex class II (MHCII) levels in Dendritic Cells. In addition, I have found an increased activation of T cells following infection of C57BL/6 mice with S. enterica serovar Typhimurium (STm) ΔsteD mutant in comparison to wild-type STm, thereby showing that SteD is an important modulator of adaptive immunity in vivo. SteD and/or its gene have a high chance of having therapeutic application. I also have obtained preliminary evidence indicating that SteD has additional functions in the manipulation of antigen-presenting cells. Therefore, I propose to use both the acute and chronic mouse models of Salmonella infection to further characterize the influence of SteD on T cell development. Furthermore, I will investigate the mechanistic and physiological significance of natural variation in the amino acid sequence of SteD among a broad range of S. enterica serovars, including the typhoid fever-causing human-adapted serovars Typhi and Paratyphi. Finally, I will explore the possible use of SteD in new formulations of DNA vaccines. These studies will provide important knowledge for the clinical application of this newly described T3SS effector.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
- View on CORDIS
- DOI: 10.3030/747392
- http://www.imperial.ac.uk/people/o.cerny/page/msca-if-supasted.html
Data: CORDIS, © European Union