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A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming

Nature Microbiology volume 1, Article number: 16174 (2016) | Download Citation

Abstract

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.

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Acknowledgements

The authors thank S. Mehta and M. Basavappa for their help with the isolation of human primary macrophages and mouse primary macrophages, respectively. The authors thank A. Ballok and A. Power Smith of Write Science Right for editing the manuscript. This work was supported by Shriners grants (nos. 87100 and 85200) and in part by NIH R33AI105902 and Cystic Fibrosis Foundation grant no. CFF#11P0. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Affiliations

  1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA

    • Arunava Bandyopadhaya
    • , Amy Tsurumi
    • , Damien Maura
    •  & Laurence G. Rahme
  2. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Arunava Bandyopadhaya
    • , Amy Tsurumi
    • , Damien Maura
    •  & Laurence G. Rahme
  3. Shriners Hospitals for Children Boston, Boston, Massachusetts 02114, USA

    • Arunava Bandyopadhaya
    • , Amy Tsurumi
    • , Damien Maura
    •  & Laurence G. Rahme
  4. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Kate L. Jeffrey

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Contributions

A.B. designed the study and conducted the experiments, performed data analysis and wrote the manuscript. A.T. performed ChIP-PCR experiments and analysis of the data and wrote the manuscript. D.M. contributed to the in vivo experiments. K.L.J. supervised ChIP-PCR experiments. L.G.R. designed the study, supervised the research and wrote the manuscript.

Competing interests

L.G.R. is the scientific founder, consultant and scientific advisory board member of Spero Therapeutics LLC (no funding was received from Spero). The other authors declare no competing financial interests.

Corresponding author

Correspondence to Laurence G. Rahme.

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DOI

https://doi.org/10.1038/nmicrobiol.2016.174

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