Staphylococcus aureus-induced immunosuppression mediated by IL-10 and IL-27 facilitates nasal colonisation

Kelly, Alanna M; Leech, John; Doyle, Sarah; McLoughlin, Rachel M.

doi:10.1371/journal.ppat.1010647

Cited by 18 publications

(7 citation statements)

References 60 publications

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“… 9 At the site of infection, S. aureus B(t) is able to induce a local immunosuppressive microenvironment that suppresses T cells to promote its persistence (term c T B ( t ) T ( t )) via various immune evasion strategies for instance, through the induction of interleukins IL-10 and IL-27, or S. aureus enterotoxins, which promote the expansion and functions of MDSCs leading to T-cell suppression. 4 , 5 , 31 , 32 A schematic representation of the model is illustrated in Figure 1 A. It is important to note that although innate immune responses do not explicitly appear in the equations, they were not ignored but were rather indirectly incorporated into the parameters describing bacterial growth, r b and κ, antigen-presenting cell (APC) activity via the parameter k b and the steady-state activity of phagocytes via the parameter c b .…”

Section: Resultsmentioning

confidence: 99%

In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

et al. 2022

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Section: Resultsmentioning

confidence: 99%

In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

et al. 2022

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“…Regarding S. aureus infection, PMNs are a major source of IL-10 during S. aureus -induced sepsis and accelerate disease progression, which is exacerbated by IFN-ɣ [ 46 , 59 ]. Myeloid cells have been shown to produce IL-10 and facilitate S. aureus persistence in the nares in an lL-27-dependent manner [ 60 ]. Furthermore, S. aureus induces IL-10 production from microglia [ 61 ] and several S. aureus PAMPs can trigger IL-10 release from monocytes and macrophages [ 62 ] in a TLR2-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, S. aureus induces IL-10 production from microglia [ 61 ] and several S. aureus PAMPs can trigger IL-10 release from monocytes and macrophages [ 62 ] in a TLR2-dependent manner. In terms of effector functions, IL-10 has been shown to attenuate macrophage proinflammatory activity [ 32 ] and Th1, Th17, and ɣδ T cell activation [ 31 , 60 , 63 ] in response to S. aureus . The latter findings align with our observations, since T cell responses were increased in IL-10 KO mice, typified by elevated IFN-ɣ and TNF production by CD4 + and ɣδ T cells.…”

Section: Discussionmentioning

confidence: 99%

IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection

Kak

Roy

Heim

et al. 2023

J Neuroinflammation

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Background Treatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival. Methods A mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined. Results Granulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production. Conclusion Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.

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“…Additionally, the adoptive transfer of proinflammatory polarized macrophages into a mouse model of S. aureus biofilm infection promoted bacterial clearance ( 30 ), suggesting that the dysfunction of resident macrophages may result from a local inhibitory environment. This is supported by the observation that the anti-inflammatory cytokine interleukin-10 (IL-10) is produced by myeloid cells in response to acute or chronic S. aureus infection ( 31 , 32 ) as well as during nasal colonization ( 33 ). IL-10 is a potent mediator that inhibits proinflammatory cytokine production and antigen processing by APCs, including macrophages, which diminishes T cell responsiveness ( 34 , 35 ).…”

Section: Introductionmentioning

confidence: 94%

Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival

Bertrand,

Shinde,

Thomas

et al. 2024

Infect Immun

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Staphylococcus aureus is a leading cause of medical device-associated biofilm infections. This is influenced by the ability of S. aureus biofilm to evade the host immune response, which is partially driven by the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that treatment of human monocyte-derived macrophages (HMDMs) with IL-10 enhanced biofilm formation, suggesting that macrophage anti-inflammatory programming likely plays an important role during the transition from planktonic to biofilm growth. To identify S. aureus genes that were important for intracellular survival in HMDMs and how this was affected by IL-10, transposon sequencing was performed. The size of the S. aureus essential genome was similar between unstimulated HMDMs and the outgrowth control (18.5% vs 18.4%, respectively, with 54.4% overlap) but increased to 22.5% in IL-10-treated macrophages, suggesting that macrophage polarization status exerts differential pressure on S. aureus . Essential genes for S. aureus survival within IL-10-polarized HMDMs were dominated by negative regulatory pathways, including nitrogen and RNA metabolism, whereas S. aureus essential genes within untreated HMDMs were enriched in biosynthetic pathways such as purine and pyrimidine biosynthesis. To explore how IL-10 altered the macrophage intracellular metabolome, targeted metabolomics was performed on HMDMs from six individual donors. IL-10 treatment led to conserved alterations in distinct metabolites that were increased (dihydroxyacetone phosphate, glyceraldehyde-3-phosphate, and acetyl-CoA) or reduced (fructose-6-phosphate, aspartic acid, and ornithine) across donors, whereas other metabolites were variable. Collectively, these findings highlight an important aspect of population-level heterogeneity in human macrophage responsiveness that should be considered when translating results to a patient population. IMPORTANCE One mechanism that Staphylococcus aureus biofilm elicits in the host to facilitate infection persistence is the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that exposure of human monocyte-derived macrophages (HMDMs) to IL-10 promotes S. aureus biofilm formation and programs intracellular bacteria to favor catabolic pathways. Examination of intracellular metabolites in HMDMs revealed heterogeneity between donors that may explain the observed variability in essential genes for S. aureus survival based on nutrient availability for bacteria within the intracellular compartment. Collectively, these studies provide novel insights into how IL-10 polarization affects S. aureus intracellular survival in HMDMs and the importance of considering macrophage heterogeneity between human donors as a variable when examining effector mechanisms.

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Staphylococcus aureus-induced immunosuppression mediated by IL-10 and IL-27 facilitates nasal colonisation

Cited by 18 publications

References 60 publications

In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection

Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival

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