SLMS Academic Careers Office

28.  Functional effects of regulatory T cells on macrophage inflammatory responses to Streptococcus pneumoniae

Supervisor Pair: Jeremy Brown and Michael Ehrenstein
Potential Student’s Home Department: Medicine

S. pneumoniae infections cause severe inflammation that exacerbates disease by contributing towards septic shock, acute lung injury and tissue damage. Inflammation in response to infective and non-infective stimuli can be regulated by a relatively uncommon T cell subset termed Regulatory T cells (Tregs). Down regualtion of inflammatory responses often worsens the outcome of infection, but recent data have shown that Tregs improve host defense during S. pneumoniae pneumonia by modulating inflammatory responses and preventing bacterial translocation into the blood. Our preliminary data shows that Tregs inhibit monocyte derived macrophage (MDM) inflammatory responses to S. pneumoniae, reducing the release of the cytokines IL1β, IL6 and TNFα. These results indicate Tregs affect the outcome of S. pneumoniae infections by modulating macrophage responses, and these interactions could be a potential target for new therapeutic strategies to reduce the morbidity and mortality of S. pneumoniae infections. We will investigate the effects of Tregs on macrophage inflammatory responses to S. pneumoniae using bacterial tools (including mutant S. pneumoniae unable to express pro-inflammatory ligands, and purified inflammatory ligands) and techniques for assessing macrophage inflammatory responses (cytokine levels, transcriptomics, qPCR, flow cytometry for activation markers) that have been developed in our laboratories. We will address the following aims:

1. Characterise in detail the effects of Tregs on monocyte derived macrophage (MDM) inflammatory responses to S. pneumoniae and its pro-inflammatory ligands using in vitro co-culture models and analysis of MDM RNA and cytokine profiles

2. Assess the mechanism(s) of Treg effects on MDM responses to S. pneumoniae using inhibition of IL10, CTLA4, and PDL-1, and to assess effects of Tregs on potential intermediary cells eg responder T cells.

3. Investigate clinically relevant consequences of Tregs interaction with MDMs during S. pneumoniae infection using transwell models of endothelium or respiratory epithelium and measurements of barrier breakdown and neutrophil recruitment

Value added perspective:

This project will bring together expertise in S. pneumoniae pathogenesis and Treg biology to develop a new area of investigation in a field that preliminary evidence suggests is very important for infectious disease but is as yet poorly defined. This will be a unique partnership in the field of S. pneumoniae pathogenesis and relatively rare in the field of bacterial pathogenesis as a whole, which should provide considerable synergy in a novel area of research with the potential to make important findings that will be published in high impact journals. Furthermore, modulation of inflammation is an increasingly important therapeutic concept for severe bacterial infections and this project is likely to identify novel targets for future immunomodulatory therapies for inflammatory bacterial infections.