期刊
NATURE MICROBIOLOGY
卷 5, 期 10, 页码 1271-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41564-020-0756-3
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资金
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [P01AI083211, R01AI125588]
- National Institute for General Medical Science [INBRE-P20GM103427-14, COBRE-1P30GM110768-01]
- Fred AMP
- Pamela Buffett Cancer Center Support Grant [P30CA036727]
Staphylococcus aureusis a leading cause of biofilm-associated prosthetic joint infection (PJI), resulting in considerable disability and prolonged treatment. It is known that host leukocyte IL-10 production is required forS. aureusbiofilm persistence in PJI. AnS. aureus bursa aurealisTn library consisting of 1,952 non-essential genes was screened for mutants that failed to induce IL-10 in myeloid-derived suppressor cells (MDSCs), which identified a critical role for bacterial lactic acid biosynthesis. We generated anS. aureus ddh/ldh1/ldh2triple Tn mutant that cannot produced- orl-lactate. Co-culture of MDSCs or macrophages withddh/ldh1/ldh2mutant biofilm produced substantially less IL-10 compared with wild-typeS. aureus, which was also observed in a mouse model of PJI and led to reduced biofilm burden. Using MDSCs recovered from the mouse PJI model and in vitro leukocyte-biofilm co-cultures, we show that bacterial-derived lactate inhibits histone deacetylase 11, causing unchecked HDAC6 activity and increased histone 3 acetylation at theIl-10promoter, resulting in enhancedIl-10transcription in MDSCs and macrophages. Finally, we show that synovial fluid of patients with PJI contains elevated amounts ofd-lactate and IL-10 compared with control subjects, and bacterial lactate increases IL-10 production by human monocyte-derived macrophages. Bacteria-derived lactate mediates inhibition of HDAC11 duringStaphylococcus aureusbiofilm infections, resulting in epigenetic changes that reprogramme the host immune response.
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