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

التفاصيل البيبلوغرافية
العنوان: Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection
المؤلفون: Sujata S. Chaudhari, Edward Seto, Amy Aldrich, Megan E. Bosch, Adam R. Karpf, David Klinkebiel, Abdulelah A. Alqarzaee, Vinai Chittezham Thomas, Casey M. Gries, Tammy Kielian, Yixuan Li, Kelsey J. Yamada, Cortney E. Heim
المصدر: Nature microbiology
سنة النشر: 2019
مصطلحات موضوعية: Microbiology (medical), Staphylococcus aureus, interleukin-10, Immunology, Mutant, macrophage, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, Article, biofilm, Histone Deacetylases, myeloid-derived suppressor cell, 03 medical and health sciences, Immune system, Genetics, medicine, Lactic Acid, prosthetic joint infection, 030304 developmental biology, lactate, 0303 health sciences, Innate immune system, 030306 microbiology, HDAC11, Chemistry, Macrophages, Myeloid-Derived Suppressor Cells, Immunity, Biofilm, Cell Biology, HDAC6, Staphylococcal Infections, S. aureus, In vitro, Biosynthetic Pathways, Biofilms, histone deacetylase, Host-Pathogen Interactions, Cytokines, Inflammation Mediators, Biomarkers
الوصف: Staphylococcus aureus (S. aureus) is a leading cause of biofilm-associated prosthetic joint infection (PJI), resulting in significant disability and prolonged treatment. It is known that host leukocyte IL-10 production is required for S. aureus biofilm persistence in PJI. A 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 a 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 (HDAC11), 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.
SUMMARY PARAGRAPH Biofilms are bacterial communities that are difficult to treat because of their tolerance to antibiotics and ability to evade immune-mediated clearance. Prosthetic joint infection (PJI), a devastating complication of arthroplasty, is characterized by biofilm formation. The current study has discovered a central role for lactic acid biosynthesis in S. aureus biofilm formation during PJI. Mechanistically, bacterial-derived lactate inhibits histone deacetylase 11 (HDAC11) activity, which causes extensive epigenetic changes at the promoters of numerous host genes, including the key anti-inflammatory cytokine Il-10. Indeed, IL-10 production by myeloid-derived suppressor cells (MDSCs) and macrophages is critical for biofilm persistence during PJI. HDAC11 inhibition by S. aureus lactate results in unchecked HDAC6 activity, a positive regulator of IL-10, thereby increasing IL-10 production by MDSCs and macrophages in vitro and in vivo. Similarly, S. aureus lactate promotes IL-10 production in human monocyte-derived macrophages following biofilm exposure. This study highlights how bacterial metabolism can influence the host immune response to promote infection persistence.
تدمد: 2058-5276
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::45b3eb4b0391cda5459489b370c3514b
https://pubmed.ncbi.nlm.nih.gov/32963374
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....45b3eb4b0391cda5459489b370c3514b
قاعدة البيانات: OpenAIRE
الوصف
تدمد:20585276