A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming.
The mechanisms by which pathogens evade elimination without affecting host fitness are not well understood. For the pathogen Pseudomonas aeruginosa, this evasion appears to be triggered by excretion of the quorum-sensing molecule 2-aminoacetophenone, which dampens host immune responses and modulates host metabolism, thereby enabling the bacteria to persist at a high burden level. Here, we examined how 2-aminoacetophenone trains host tissues to become tolerant to a high bacterial burden, without compromising host fitness. We found that 2-aminoacetophenone regulates histone deacetylase 1 expression and activity, resulting in hypo-acetylation of lysine 18 of histone H3 at pro-inflammatory cytokine loci. Specifically, 2-aminoacetophenone induced reprogramming of immune cells occurs via alterations in histone acetylation of immune cytokines in vivo and in vitro. This host epigenetic reprograming, which was maintained for up to 7 days, dampened host responses to subsequent exposure to 2-aminoacetophenone or other unrelated pathogen-associated molecules. The process was found to involve a distinct molecular mechanism of host chromatin regulation. Inhibition of histone deacetylase 1 prevented the immunomodulatory effects of 2-aminoacetophenone. These observations provide the first mechanistic example of a quorum-sensing molecule regulating a host epigenome to enable tolerance of infection. These insights have enormous potential for developing preventive treatments against bacterial infections.
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, USA.
Arunava
A
Bandyopadhaya
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, USA.
Amy
http://orcid.org/0000-0001-7678-169X
A
Tsurumi
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, USA.
Damien
D
Maura
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Kate L
KL
Jeffrey
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, USA.
Laurence G
LG
Rahme
D000098:Acetophenones / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007108:Immune Tolerance; D051379:Mice; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D000074084:THP-1 Cells
D000098:Acetophenones; D016207:Cytokines; C055495:2-aminoacetophenone; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
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