Lactate production by <i>Staphylococcus aureus</i> biofilm inhibits HDAC11 to reprogram the host immune response during persistent infection

Abstract Staphylococcus aureus (S. aureus) is a leading cause of prosthetic joint infection (PJI) typified by biofilm formation. Our laboratory has identified preferential myeloid-derived suppressor cell (MDSC) recruitment as critical mechanism for persistence, MDSCs are main source IL-10. We screened the Nebraska Transposon Mutant Library to identify S. mutants impaired in their ability trigger MDSC IL-10 production. Significant hits lactate biosynthesis were identified. A Δddh/ldh1/ldh2 mutant, defective both D- and L-lactate production, decreased leukocyte expression biofilm-associated monocytes reprogrammed pro-inflammatory state, resulting reduced burden. Histone acetylation plays central role regulating gene histone deacetylase (HDAC) activity was significantly increased leukocytes recovered from mice infected with compared WT, global 3 (H3) at promoter Δddh/ldh1/ldh2-infected mice. Lactate inhibited HDAC11, unchecked HDAC6, positive regulator Il-10 transcription, macrophages produced less when treated HDAC6 inhibitor tubastatin during co-culture WT but not biofilm. D-lactate elevated synovial fluid patients PJI aseptic controls promoted production human monocyte-derived macrophages. Collectively, lactate-mediated inhibition HDAC11 infection, epigenetic changes that reprogram host immune response.