Abstract
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
Highlights
The gram-positive bacterium Staphylococcus aureus is an extracellular pathogen with the ability to invade and persist within host cells
At day 4, a still early time point of T cell differentiation, substantial fractions of the cells cultured under T helper 1 (Th1)- and T helper 17 (Th17)-polarizing conditions already showed IFNγ and IL-17A expression, respectively (Figures S1B,C), in line with recent studies involving in vitro T cell differentiation cultures [29, 30]
The CD4+ T cells were a mixture of memory and naïve CD4+ T cells in all studies, and IL17A secretion upon stimulation with alpha-toxin could only be observed in Th17-polarized cells, suggesting that memory T cells were most probably the source of IFNγ and IL-17A production in alpha-toxin-stimulated CD4+ T cells
Summary
The gram-positive bacterium Staphylococcus aureus is an extracellular pathogen with the ability to invade and persist within host cells. Many attempts have been made, there is currently no vaccine available that can prevent S. aureus infections in humans This might be due to efficient bacterial virulence and immune evasion mechanisms that enable S. aureus to escape immune surveillance by the host [6]. Another study suggested that immunization with a multicomponent vaccine protected mice in a kidney abscess model as well as a peritonitis model through the synergistic action of Th17 cells and antibodies [9] These and other examples clearly show that, depending on the vaccination approach and the utilized infection model, different CD4+ effector T cell subsets can confer protection against S. aureus [10, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
