Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection

• Published in: Nature microbiology Vol. 5; no. 10; pp. 1271 - 1284
• Main Authors: Heim, Cortney E., Bosch, Megan E., Yamada, Kelsey J., Aldrich, Amy L., Chaudhari, Sujata S., Klinkebiel, David, Gries, Casey M., Alqarzaee, Abdulelah A., Li, Yixuan, Thomas, Vinai C., Seto, Edward, Karpf, Adam R., Kielian, Tammy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 38/39; 38/91; 631/250/255; 631/250/262; 631/326/41; 631/326/46; 64/110; 64/60; Acetylation; Bacteria; Biofilms; Biomarkers; Biomedical and Life Sciences; Biosynthetic Pathways; Cell culture; Cytokines - metabolism; Epigenetics; Histone deacetylase; Histone Deacetylases - metabolism; Host-Pathogen Interactions - immunology; Immune response; Infectious Diseases; Inflammation Mediators - metabolism; Interleukin 10; Joint diseases; Lactic acid; Lactic Acid - metabolism; Life Sciences; Macrophages; Macrophages - immunology; Macrophages - metabolism; Medical Microbiology; Microbiology; Monocytes; Mutants; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Parasitology; Penicillin; Staphylococcal Infections - immunology; Staphylococcal Infections - metabolism; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - physiology; Suppressor cells; Synovial fluid; Transcription; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-020-0756-3

Staphylococcus aureus is 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 for S. aureus biofilm persistence in PJI. An S. aureus bursa aurealis Tn 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 an S. aureus ddh/ldh1/ldh2 triple Tn mutant that cannot produce d - or l -lactate. Co-culture of MDSCs or macrophages with ddh/ldh1/ldh2 mutant biofilm produced substantially less IL-10 compared with wild-type S. 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 the Il-10 promoter, resulting in enhanced Il-10 transcription in MDSCs and macrophages. Finally, we show that synovial fluid of patients with PJI contains elevated amounts of d -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 during Staphylococcus aureus biofilm infections, resulting in epigenetic changes that reprogramme the host immune response.