| dc.description.abstract | Staphylococcus aureus bloodstream infection is a common and life-threatening condition. Treatment outcomes are poor, suboptimal clinical management is common, antimicrobial resistance continues to emerge, and there are few new agents in the drug discovery pipeline. There is an urgent need for novel methods of preventing and treating S. aureus infection. A lack of understanding of protective immunity or its correlates has greatly impeded progress in the development of rationally-designed anti-S. aureus vaccines. This project set out to characterise the pathogen, its clinical impact on patients, and the adaptive immune response it induced in humans, with a particular focus on T lymphocytes. The clinical characteristics, management and outcomes of adult patients with S. aureus and E. coli bloodstream infection (SA-BSI and EC-BSI) were contrasted. The bulk of S. aureus disease was attributable to methicillin-susceptible S. aureus and infection was frequently community-acquired. S. aureus's capacity to cause severe disease in otherwise healthy people and to follow a complicated course distinguished it from E. coli. Failure, relapse or death was seen in a large proportion of SA-BSI, whereas all E. coli infections were easily and rapidly cured. Healthcare resource utilisation was significantly greater in S. aureus infection. Of concern, clinical management of SA-BSI was suboptimal in over half of cases, and occured when patients were not under the care of infection specialists. There was considerable genotypic heterogeneity, particularly in MSSA, in invasive S. aureus isolates. Despite this variety in lineage, genes for several cell-wall antigens were present and conserved on next-generation genome sequencing, which may be promising for vaccine development. A critical problem for vaccine development has been the lack of known mechanisms or correlates of protective immunity to S. aureus infection in humans. There is considerable doubt that induction of humoral immunity alone will be sufficient to confer protection against S. aureus infection. It is now widely accepted that a vaccine with multiple antigens, that targets both cellular and humoral immunity is required. However, it is unknown which specific cells to target in next-generation vaccines. Clinical observations and data from mouse models support a key role for T helper lymphocytes producing IFNγ or IL-17 in anti-staphylococcal immunity. Despite these clues, it was not known if human T cells could recognise and respond to S. aureus antigens, and there had been no previous investigation of human cell-mediated immune response in invasive infection. This project described, for the first time in humans, the adaptive immune response in the early recovery period of S. aureus bloodstream infection. In addition to antibody responses, human αβ (CD4+ and CD8+), but not γδ+ lymphocytes recognised and responded to S. aureus during recovery from bloodstream infection. This response was primarily Th1-mediated, with a lesser contribution from Th17 cells. Th1 immune memory was formed or re-activated during systemic infection. Similar pathogen-specific T helper cell activation was not seen in patients with E. coli bloodstream infection, implying a substantial difference between the role of T cells in these two bacterial infections. A S. aureus antigen-specific Th1/17 signature thus seems particular to recovery from invasive staphylococcal disease and, similar to animal models, may be a correlate of protective immunity. The final part of this work successfully developed a model assay to measure T cell immunogenicity of specific S. aureus antigens (and T cell-directed adjuvants) using blood donor buffy coats and clumping factor A as a model antigen. This assay can be used to map T helper cell responses over the course of infection in future SA-BSI patients to correlate relative potency of T cell activation with clinical outcome. These preliminary findings are a substantial step forward in understanding how T cells react during S. aureus infection in real patients – knowledge fundamental to manipulating their activity in host-targeted therapeutics. | en |
