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PhD In Infection & Immunity - Profiling superantigen-induced immunosupression of unconventional T cells during severe sepsis

Project Description

Sepsis is a life-threatening illness that is triggered by an exaggerated immune response to severe infection. This unbalanced reaction induces hyperinflammation, shock and organ dysfunction that forms the primary cause of death in hospitalised patients. Although survival rates are increasing following treatment at acute stages, patients often display sustained immunosuppression post-treatment and an increased susceptibility to secondary infections. Research has determined that such immune degeneration is a consequence of depleted T cell populations which provide a crucial defence mechanism against viral and microbial infections. The causal factors behind sepsis-induced “immunoparalysis” are poorly understood and further research is essential in order to develop therapeutic interventions that improve long-term survival and reduce costs for the NHS.

This proposal is based on the hypothesis that potent toxins secreted by virulent microorganisms (bacterial “superantigens” (SAgs)) contribute to sepsis-induced immunoparalysis by suppressing “unconventional”, antimicrobial T cell populations. Two types of gram-positive bacteria, Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes), produce a range of SAgs which have been linked with the induction of T cell immunosuppression. In this respect, SAgs display a unique ability to “cross-link” pathogen-sensing receptors on the T cell surface to MHC class II molecules found on antigen-presenting cells. Such contact engages excessive T cell activation and pronounced “exhaustion” or death in these cells, which serves to weaken the immune system by exposing “holes” in our protective immunity. Unconventional T cells (γδ T cells, mucosal-associated invariant T (MAIT) cells) can be targeted by SAgs and their consequential depletion would serve to diminish host antimicrobial defence mechanisms. Whilst it is unclear if all known SAgs can target MAIT and γδ T cells, it is apparent that these T cell types are depleted in the blood of septic patients. However, a pathogenic link between bacterial SAgs and unconventional T cell immunosuppression in sepsis has yet to be determined.

We will aim to investigate a mechanistic link between bacterial SAgs and suppressed MAIT and γδ T cell populations in sepsis. This will be accomplished by examining direct interactions afforded by a panel of SAgs (from S. aureus and S. pyogenes) and T cell receptors (TCRs) located on the surface of MAIT and γδ T cells. Using human peripheral blood mononuclear cells from recruited healthy individuals, we will scrutinise SAg-driven T cell activation and exhaustion in MAIT and γδ T cells. Novel or common interactions between SAgs and MAIT and/or γδ T cells that drive cellular immunosuppression will be interrogated further at the genetic level using established techniques. This process will be performed in healthy individuals and in recruited patients with severe sepsis in order to determine if certain TCR “clonotypes” from these T cell subsets are selectively depleted by SAgs in sepsis. This work will lay the foundation for a potential pathogenic link between SAgs and sepsis-induced immunoparalysis and could inform the design of therapeutic interventions that reverse T cell immunosuppression and improve long-term outcome.

Funding Notes

The studentship is generously funded by the School of Medicine
Full UK/EU tuition fees
Doctoral stipend matching UK Research Council National Minimum
Additional funding is available over the course of the programme and will cover costs such as research consumables and training.
Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)


In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2019). This will take you to the application portal.
Candidates are only permitted to submit one application but may select a maximum of three projects, ranked in order of preference in the ‘Research Proposal’ section of the application. In order to be considered candidates must submit the following information:

• Supporting statement
• CV
• Qualification certificates
• References x 2
• Proof of English language (if applicable)

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