Lactate production byStaphylococcus aureusbiofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection

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.