Abstract
Dendritic cells (DCs) are key players of the immune system and thus a target for immune evasion by pathogens. We recently showed that the virulence factors phenol-soluble-modulins (PSMs) produced by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains induce tolerogenic DCs upon Toll-like receptor activation via the p38-CREB-IL-10 pathway in vitro. Here, we addressed the hypothesis that S. aureus PSMs disturb the adaptive immune response via modulation of DC subsets in vivo. Using a systemic mouse infection model we found that S. aureus reduced the numbers of splenic DC subsets, mainly CD4+ and CD8+ DCs independently of PSM secretion. S. aureus infection induced upregulation of the C-C motif chemokine receptor 7 (CCR7) on the surface of all DC subsets, on CD4+ DCs in a PSM-dependent manner, together with increased expression of MHCII, CD86, CD80, CD40, and the co-inhibitory molecule PD-L2, with only minor effects of PSMs. Moreover, PSMs increased IL-10 production in the spleen and impaired TNF production by CD4+ DCs. Besides, S. aureus PSMs reduced the number of CD4+ T cells in the spleen, whereas CD4+CD25+Foxp3+ regulatory T cells (Tregs) were increased. In contrast, Th1 and Th17 priming and IFN-γ production by CD8+ T cells were impaired by S. aureus PSMs. Thus, PSMs from highly virulent S. aureus strains modulate the adaptive immune response in the direction of tolerance by affecting DC functions.
Highlights
The Gram-positive bacterium Staphylococcus aureus is a frequent member of the human microbiota, but it is the most common cause of bloodstream infections and the leading cause of more than 50% of skin and soft-tissue infections worldwide [1, 2]
The number of dendritic cell (DC) was significantly reduced at 24 h (PBS: 3.56 ± 0.92 × 106; wild type (WT): 1.47 ± 0.43 × 106, αβδ 1.75 ± 0.13 × 106) and even more at 72 h pi with the S. aureus USA300 WT or the USA300 αβδ mutant strain compared to PBS treatment (PBS: 2.38 ± 1.04 × 106; WT: 0.36 ± 0.39 × 106, αβδ 0.69 ± 0.52 × 106) [Figures 1A,B]
Similar results were obtained for CD4+ and CD8+ DCs with significantly reduced cell numbers 24 and 72 h pi with S. aureus USA300 WT and αβδ, which was not observed for DN DCs (Figures 1C–E, Figure S3)
Summary
The Gram-positive bacterium Staphylococcus aureus is a frequent member of the human microbiota, but it is the most common cause of bloodstream infections (bacteremia) and the leading cause of more than 50% of skin and soft-tissue infections worldwide [1, 2]. CA-MRSA strains efficiently evade the host’s innate and adaptive immune system by the expression of a great variety of virulence factors, like Panton-Valentine Leukocidin, α-toxin, and phenol-soluble modulin (PSM) peptides, which are highly secreted by these strains [1, 3,4,5]. PSMs first attract innate immune cells like neutrophils, macrophages, and dendritic cells (DCs) by binding to the formyl peptide receptor 2 (FPR2) [5, 7,8,9]. Α-type PSMs were shown to lyse neutrophils, monocytes and erythrocytes, but not DCs, via membrane perturbation, thereby evading the innate immune response [6, 7, 9,10,11]. S. aureus infection impairs proliferation of B cells and T cells, which prevents the establishment of protective immune responses [4]
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