PSM Peptides From Community-Associated Methicillin-Resistant Staphylococcus aureus Impair the Adaptive Immune Response via Modulation of Dendritic Cell Subsets in vivo

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 (T regs ) 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.

Staphylococcus aureus Protein A Induces Human Regulatory T Cells Through Interaction With Antigen-Presenting Cells

“…So far, we can only speculate whether SpA, similar to PSMa (41,42,54) and staphylococcal enterotoxins (62) favors the generation of tolerogenic DC (tDC) or myeloid suppressor cells, cell subsets with strong Treg-inducing capacities (63,64). While (65) as important player in Sa-triggered Treg induction.…”

“…Several groups demonstrated a potential role of Tregs in postinfectious arthritis following Sa infection (37)(38)(39) and in atopic dermatitis (40). Furthermore, the Sa virulence factor phenolsoluble modulin (PSMa) was shown to modulate human and mouse APC surface marker expression and cytokine secretion to induce Treg in vitro and in vivo (41)(42)(43). Moreover, it has been shown that staphylococcal superantigens induce human Tregs in PBMC (44) and convert peripheral CD4 + CD25 -T cells to a regulatory phenotype with suppressive function (45,46).…”

Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses

“…Other secreted proteins result in allergic responses or favor regulatory T cell differentiation ( 13 – 15 ). Very recently, Richardson et al have shown that staphylococcal phenol-soluble-modulins inhibit in vivo Th1 and Th17 polarization during systemic S. aureus infection ( 16 ). One major virulence factor of S. aureus is alpha-toxin (aka alpha-hemolysin, hla), which was first described for its lytic activity toward rabbit erythrocytes ( 17 ).…”

Verificação Da Temperatura De Distribuição De Refeições Quentes Ofertadas Em Uma Instituição De Longa Permanência Para Idosos E a Correlação Com O Crescimento Microbiológico

“…Muitas das infecções são causadas por produção de biofilme, o qual mostra evidências emergentes que sugerem que o crescimento dessas comunidades microbianas mistas pode levar a alteração dos perfis de tolerância antimicrobiana. aureus tem emergido na comunidade e aumentando tanto a frequência quanto à gravidade de infecções causadas por esta bactéria(RICHARDSON et al, 2019). De fato, níveis alarmantes de resistência já são detectados em algumas localizações, e alguns isolados de S. aureus possuem resistência para fármacos considerados como de última escolha, como a vancomicina (OLUFUNMISO; TOLULOPE;ROGER, 2017;VANEGAS MUNERA et al, 2017).…”