Adjuvants, Immunologic, Adoptive Transfer, Adult, Aged, Animals, Antigens, Female, Humans, Immunologic Memory, Interleukin-17, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Staphylococcal Infections, Staphylococcal Skin Infections, Staphylococcus aureus, Th1 Cells
This project was supported primarily by a Health Research Board, Health Research Award (HRA_POR/2012/104), a Wellcome Trust Research Career Development Fellowship (WT086515MA) to RMM and in part by a Science Foundation Ireland Investigator Award (12/IA/1421) to ECL. http://www. hrb.ie/; http://www.wellcome.ac.uk; http://www.sfi.ie/.
Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.
Medicine and Health Sciences
Brown AF, Murphy AG, Lalor SJ, Leech JM, O'Keeffe KM, Mac Aogáin M, O'Halloran DP, Lacey KA, Tavakol M, Hearnden CH, Fitzgerald-Hughes D, Humphreys H, Fennell JP, van Wamel WJ, Foster TJ, Geoghegan JA, Lavelle EC, Rogers TR, McLoughlin RM. Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection. PLoS Pathogens. 2015;11(11):e1005226.
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