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Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

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 - PLoS Pathog. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Host-Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Prior exposure to S. aureus increases IFNγ secretion by CD4+ and CD8+ T cells during subsequent infection.Groups of mice were exposed to S. aureus (5x108 CFU) via an i.p. injection on d 0, 7 and 14. Prior exposed mice were then re-challenged with an i.p. injection of S. aureus (5x108 CFU) on d 35 alongside a control group of naïve mice. At indicated time points post-challenge the peritoneal cavity was lavaged with PBS to assess IFNγ secretion by ELISA (A). n = 15 per group. At 3 h post challenge peritoneal cells were isolated to assess the proportions of IFNγ-producing CD4+ and CD8+ T cells using flow cytometry (B). Results expressed as mean ± SEM and representative FACS plots. n = 5 per group. *p<0.05, **p<0.005, ***p<0.001.
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ppat.1005226.g001: Prior exposure to S. aureus increases IFNγ secretion by CD4+ and CD8+ T cells during subsequent infection.Groups of mice were exposed to S. aureus (5x108 CFU) via an i.p. injection on d 0, 7 and 14. Prior exposed mice were then re-challenged with an i.p. injection of S. aureus (5x108 CFU) on d 35 alongside a control group of naïve mice. At indicated time points post-challenge the peritoneal cavity was lavaged with PBS to assess IFNγ secretion by ELISA (A). n = 15 per group. At 3 h post challenge peritoneal cells were isolated to assess the proportions of IFNγ-producing CD4+ and CD8+ T cells using flow cytometry (B). Results expressed as mean ± SEM and representative FACS plots. n = 5 per group. *p<0.05, **p<0.005, ***p<0.001.

Mentions: Using a previously described [30] murine model of recurrent S. aureus exposure, followed by a period of recovery prior to subsequent challenge, we identified that local production of IFNγ in the peritoneal cavity was significantly increased soon after challenge of prior exposed mice, while it remained undetectable in naïve mice infected for the first time (Fig 1A). Twenty percent of CD4+ and 10% of CD8+ T cells in the peritoneal cavity were making IFNγ (Fig 1B). We have previously shown that γδ+ T cells were not contributing to IFNγ production in this model [30]. Similarly, there was no evidence for IFNγ production by NK cells. Thus, CD4+ T cells were the primary source of IFNγ in the prior exposed mice. CD4+ T cells–but not CD8+ T cells–with the capacity for IFNγ production were sustained in the peritoneum for up to 5 d post-challenge (S1A Fig). CD4+IFNγ+ (Th1) cells were evident in the spleen by 12 h post-challenge, with no similar systemic expansion of CD8+ cells (S1B Fig). Neither CD4+ nor CD8+ IFNγ-producing cells were found in the draining mediastinal lymph nodes (MLN).


Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection.

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 - PLoS Pathog. (2015)

Prior exposure to S. aureus increases IFNγ secretion by CD4+ and CD8+ T cells during subsequent infection.Groups of mice were exposed to S. aureus (5x108 CFU) via an i.p. injection on d 0, 7 and 14. Prior exposed mice were then re-challenged with an i.p. injection of S. aureus (5x108 CFU) on d 35 alongside a control group of naïve mice. At indicated time points post-challenge the peritoneal cavity was lavaged with PBS to assess IFNγ secretion by ELISA (A). n = 15 per group. At 3 h post challenge peritoneal cells were isolated to assess the proportions of IFNγ-producing CD4+ and CD8+ T cells using flow cytometry (B). Results expressed as mean ± SEM and representative FACS plots. n = 5 per group. *p<0.05, **p<0.005, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4634925&req=5

ppat.1005226.g001: Prior exposure to S. aureus increases IFNγ secretion by CD4+ and CD8+ T cells during subsequent infection.Groups of mice were exposed to S. aureus (5x108 CFU) via an i.p. injection on d 0, 7 and 14. Prior exposed mice were then re-challenged with an i.p. injection of S. aureus (5x108 CFU) on d 35 alongside a control group of naïve mice. At indicated time points post-challenge the peritoneal cavity was lavaged with PBS to assess IFNγ secretion by ELISA (A). n = 15 per group. At 3 h post challenge peritoneal cells were isolated to assess the proportions of IFNγ-producing CD4+ and CD8+ T cells using flow cytometry (B). Results expressed as mean ± SEM and representative FACS plots. n = 5 per group. *p<0.05, **p<0.005, ***p<0.001.
Mentions: Using a previously described [30] murine model of recurrent S. aureus exposure, followed by a period of recovery prior to subsequent challenge, we identified that local production of IFNγ in the peritoneal cavity was significantly increased soon after challenge of prior exposed mice, while it remained undetectable in naïve mice infected for the first time (Fig 1A). Twenty percent of CD4+ and 10% of CD8+ T cells in the peritoneal cavity were making IFNγ (Fig 1B). We have previously shown that γδ+ T cells were not contributing to IFNγ production in this model [30]. Similarly, there was no evidence for IFNγ production by NK cells. Thus, CD4+ T cells were the primary source of IFNγ in the prior exposed mice. CD4+ T cells–but not CD8+ T cells–with the capacity for IFNγ production were sustained in the peritoneum for up to 5 d post-challenge (S1A Fig). CD4+IFNγ+ (Th1) cells were evident in the spleen by 12 h post-challenge, with no similar systemic expansion of CD8+ cells (S1B Fig). Neither CD4+ nor CD8+ IFNγ-producing cells were found in the draining mediastinal lymph nodes (MLN).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Host-Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus