Mesenchymal stem cells (MSCs) regulate lung inflammation and enhance bacterial clearance and survival in preclinical models of pneumonia and sepsis, making them an attractive novel treatment for bacterial lung infection resistant to antibiotic therapy. Regulatory T cells (Tregs) are a subset of CD4+ T cells acknowledged to be important in maintaining the fine balance of immune responses during bacterial infection. Their precise role in streptococcal and pseudomonal lung infection is undefined and their interaction with MSCs in the context of bacterial infection is undetermined. This thesis explores the impact of MSC on host immunity in bacterial lung infection. The work described in this thesis involves an investigation of MSC antimicrobial effect in established experimental mouse models of Gram positive and Gram negative bacterial lung infection and exploration of the potential role of Tregs contributing to the observed antimicrobial effects.
Systemic treatment with MSCs reduced bacterial burden in lung and bronchoalveolar lavage (BAL) following intranasal infection with S. pneumoniae and P. aeruginosa. Levels of pro-inflammatory cytokines in lung (TNF-α, IL-6, IFN-γ and IL-17F) and BAL (IL-6) were also significantly reduced. Immunity shifted away from a TH1/TH17 towards a TH2 response in mice infected with S. pneumoniae and then treated with MSCs. Depletion of Tregs in an inducible Foxp3.DTR knockout mouse experimental model prior to infection with S. pneumoniae resulted in a significant increase in lung bacterial burden, suggesting that Tregs are beneficial to the host response to this bacterium. In contrast, Treg depletion during P. aeruginosa lung infection did not impact on bacterial burden or inflammatory response, suggesting no role for Tregs in the host response to this bacterium. Following infection with S. pneumoniae, bacterial burden and inflammatory response was greater in MSC treated Treg-deplete mice compared with the Treg-replete cohort. This suggests that the MSC protective effect for this lung pathogen may be partially Treg dependent. In contrast, in the P. aeruginosa lung infection model, the MSC protective effect was preserved following Treg depletion, suggesting that MSC protective effect is independent of Tregs.