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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) Cite this article

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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.

Pathogens have evolved mechanisms for evading eradication by the dynamic immune systems of their hosts1,2. The establishment and maintenance of bacterial infections rely on the pathogen's ability to breach the host's innate immune responses3. Immune-driven resistance is the prevailing defence strategy against infection. However, organisms can also defend themselves through a different defence strategy, namely tolerance, defined as the ability to limit pathogen damage without controlling pathogen burden4,5. Tolerance is an evolutionarily conserved defence strategy shared by diverse plants and animals, including humans6. In tolerance (or resilience), a host copes with a pathogenic encounter without a reduction in fitness4,6,7 and avoids harmful inflammatory responses that can occur during the immune-driven resistance strategy8. The resistance and tolerance defence strategies have different ecological and evolutionary consequences: resistance reduces pathogen presence, whereas tolerance allows pathogen prevalence. Our understanding of the biological mechanisms mediating the mutual pathogen–host adaptation and the causes and consequences of variation in host tolerance is limited.

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Figure 1: 2-AA pretreatment modulates activation of NF-κB and cytokines, and promotes long-term immunosuppression.
Figure 2: 2-AA pretreatment modulates histone acetylation.
Figure 3: 2-AA pretreatment modulates HAT/HDAC activity and promotes HDAC1 accumulation.
Figure 4: HDAC1 inhibition reinstates histone acetylation and NF-κB activation and modulates cytokine secretion.
Figure 5: HDAC1 is important for 2-AA-mediated host tolerance training in vivo.

References

  1. Ruby, T. & Monack, D. M. At home with hostility: How do pathogenic bacteria evade mammalian immune surveillance to establish persistent infection? F1000 Biol. Rep. 3, 1 (2011).

    PubMed  PubMed Central  Google Scholar 

  2. Reddick, L. E. & Alto, N. M. Bacteria fighting back: how pathogens target and subvert the host innate immune system. Mol. Cell 54, 321–328 (2014).

    Article  CAS  Google Scholar 

  3. Finlay, B. B. & McFadden, G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124, 767–782 (2006).

    Article  CAS  Google Scholar 

  4. Ayres, J. S. & Schneider, D. S. Tolerance of infections. Annu. Rev. Immunol. 30, 271–294 (2012).

    Article  CAS  Google Scholar 

  5. Soares, M. P., Gozzelino, R. & Weis, S. Tissue damage control in disease tolerance. Trends Immunol. 35, 483–494 (2014).

    Article  CAS  Google Scholar 

  6. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  Google Scholar 

  7. Read, A. F., Graham, A. L. & Raberg, L. Animal defenses against infectious agents: is damage control more important than pathogen control. PLoS Biol. 6, e000004 (2008).

    Article  Google Scholar 

  8. Schmid-Hempel, P. Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence. Phil. Trans. R. Soc. Lond. B 364, 85–98 (2009).

    Article  Google Scholar 

  9. Mehta, S. & Jeffrey, K. L. Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity. Immunol. Cell Biol. 93, 233–244 (2015).

    Article  CAS  Google Scholar 

  10. Netea, M. G., Latz, E., Mills, K. H. & O'Neill, L. A. Innate immune memory: a paradigm shift in understanding host defense. Nat. Immunol. 16, 675–679 (2015).

    Article  CAS  Google Scholar 

  11. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    Article  Google Scholar 

  12. Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    Article  Google Scholar 

  13. Bandyopadhaya, A. et al. The quorum sensing volatile molecule 2-amino acetophenon modulates host immune responses in a manner that promotes life with unwanted guests. PLoS Pathogens 8, e1003024 (2012).

    Article  CAS  Google Scholar 

  14. Tzika, A. A. et al. A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle. PLoS ONE 8, e74528 (2013).

    Article  CAS  Google Scholar 

  15. Kesarwani, M. et al. A quorum sensing regulated small volatile molecule reduces acute virulence and promotes chronic infection phenotypes. PLoS Pathogens 7, e1002192 (2011).

    Article  CAS  Google Scholar 

  16. Cox, C. D. & Parker, J. Use of 2-aminoacetophenone production in identification of Pseudomonas aeruginosa. J. Clin. Microbiol. 9, 479–484 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Dickschat, J. S., Martens, T., Brinkhoff, T., Simon, M. & Schulz, S. Volatiles released by a Streptomyces species isolated from the North Sea. Chem. Biodivers. 2, 837–865 (2005).

    Article  CAS  Google Scholar 

  18. Yamada-Onodera, K., Takase, Y. & Tani, Y. Purification and characterization of 2-aminoacetophenone reductase of newly isolated Burkholderia sp. J. Biosci. Bioeng. 104, 416–419 (2007).

    Article  CAS  Google Scholar 

  19. Thiel, V. et al. Identification and biosynthesis of tropone derivatives and sulfur volatiles produced by bacteria of the marine Roseobacter clade. Org. Biomol. Chem. 8, 234–246 (2010).

    Article  CAS  Google Scholar 

  20. Scott-Thomas, A. J. et al. 2-Aminoacetophenone as a potential breath biomarker for Pseudomonas aeruginosa in the cystic fibrosis lung. BMC Pulm. Med. 10, 56 (2010).

    Article  Google Scholar 

  21. Rutherford, S. T. & Bassler, B. L. Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb. Perspect Med. 2, a012427 (2012).

    Article  Google Scholar 

  22. Parker, C. T. & Sperandio, V. Cell-to-cell signalling during pathogenesis. Cell Microbiol. 11, 363–369 (2009).

    Article  CAS  Google Scholar 

  23. Deziel, E. et al. The contribution of MvfR to Pseudomonas aeruginosa pathogenesis and quorum sensing circuitry regulation: multiple quorum sensing-regulated genes are modulated without affecting lasRI, rhlRI or the production of N-acyl-l-homoserine lactones. Mol. Microbiol. 55, 998–1014 (2005).

    Article  CAS  Google Scholar 

  24. Xiao, G. et al. MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands. Mol. Microbiol. 62, 1689–1699 (2006).

    Article  CAS  Google Scholar 

  25. Que, Y. A. et al. A quorum sensing small volatile molecule promotes antibiotic tolerance in bacteria. PLoS ONE 8, e80140 (2013).

    Article  Google Scholar 

  26. Bierne, H., Hamon, M. & Cossart, P. Epigenetics and bacterial infections. Cold Spring Harb. Perspect Med. 2, a010272 (2012).

    Article  Google Scholar 

  27. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  Google Scholar 

  28. Hamon, M. A. & Cossart, P. Histone modifications and chromatin remodeling during bacterial infections. Cell Host Microbe. 4, 100–109 (2008).

    Article  CAS  Google Scholar 

  29. Villagra, A., Sotomayor, E. M. & Seto, E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene 29, 157–173 (2010).

    Article  CAS  Google Scholar 

  30. Halili, M. A. et al. Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS. J. Leukoc. Biol. 87, 1103–1114 (2010).

    Article  CAS  Google Scholar 

  31. Nishioka, C. et al. MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk. Res. 32, 1382–1392 (2008).

    Article  CAS  Google Scholar 

  32. Lobera, M. et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat. Chem. Biol. 9, 319–325 (2013).

    Article  CAS  Google Scholar 

  33. Malvaez, M. et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc. Natl Acad. Sci. USA 110, 2647–2652 (2013).

    Article  CAS  Google Scholar 

  34. Balasubramanian, S. et al. A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia 22, 1026–1034 (2008).

    Article  CAS  Google Scholar 

  35. Lee, J. H. et al. Development of a histone deacetylase 6 inhibitor and its biological effects. Proc. Natl Acad. Sci. USA 110, 15704–15709 (2013).

    Article  CAS  Google Scholar 

  36. Avalos, J. L., Bever, K. M. & Wolberger, C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol. Cell 17, 855–868 (2005).

    Article  CAS  Google Scholar 

  37. Rahme, L. G. et al. Common virulence factors for bacterial pathogenicity in plants and animals. Science 268, 1899–1902 (1995).

    Article  CAS  Google Scholar 

  38. Rahme, L. G. et al. Plants and animals share functionally common bacterial virulence factors. Proc. Natl Acad. Sci. USA 97, 8815–8821 (2000).

    Article  CAS  Google Scholar 

  39. Lau, G. W. et al. The Drosophila melanogaster toll pathway participates in resistance to infection by the Gram-negative human pathogen Pseudomonas aeruginosa. Infect. Immun. 71, 4059–4066 (2003).

    Article  CAS  Google Scholar 

  40. Mahajan-Miklos, S., Tan, M. W., Rahme, L. G. & Ausubel, F. M. Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa–Caenorhabditis elegans pathogenesis model. Cell 96, 47–56 (1999).

    Article  CAS  Google Scholar 

  41. Snitkin, E. S. & Segre, J. A. Pseudomonas aeruginosa adaptation to human hosts. Nat. Genet. 47, 2–3 (2015).

    Article  CAS  Google Scholar 

  42. Garcia-Garcia, J. C., Barat, N. C., Trembley, S. J. & Dumler, J. S. Epigenetic silencing of host cell defense genes enhances intracellular survival of the Rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathogens 5, e1000488 (2009).

    Article  Google Scholar 

  43. Paschos, K. & Allday, M. J. Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol. 18, 439–447 (2010).

    Article  CAS  Google Scholar 

  44. Aung, H. T. et al. LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression. FASEB J. 20, 1315–1327 (2006).

    Article  CAS  Google Scholar 

  45. Eskandarian, H. A. et al. A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection. Science 341, 1238858 (2013).

    Article  Google Scholar 

  46. Quintin, J., Cheng, S. C., van der Meer, J. W. & Netea, M. G. Innate immune memory: towards a better understanding of host defense mechanisms. Curr. Opin. Immunol. 29, 1–7 (2014).

    Article  CAS  Google Scholar 

  47. Li, R. et al. Attenuated Bordetella pertussis protects against highly pathogenic influenza A viruses by dampening the cytokine storm. J. Virol. 84, 7105–7113 (2010).

    Article  CAS  Google Scholar 

  48. Khajanchi, B. K., Kirtley, M. L., Brackman, S. M. & Chopra, A. K. Immunomodulatory and protective roles of quorum-sensing signaling molecules N-acyl homoserine lactones during infection of mice with Aeromonas hydrophila. Infect. Immun. 79, 2646–2657 (2011).

    Article  CAS  Google Scholar 

  49. Wheeler, D. S. et al. Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis. Shock 30, 267–273 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yan, Q. et al. Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proc. Natl Acad. Sci. USA 109, 14140–14145 (2012).

    Article  CAS  Google Scholar 

  51. Ploeger, D. T. et al. Cell plasticity in wound healing: paracrine factors of M1/ M2 polarized macrophages influence the phenotypical state of dermal fibroblasts. Cell Commun. Signal. 11, 29 (2013).

    Article  CAS  Google Scholar 

  52. Shechter, D., Dormann, H. L., Allis, C. D. & Hake, S. B. Extraction, purification and analysis of histones. Nat. Protoc. 2, 1445–1457 (2007).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations

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

    Arunava Bandyopadhaya, Amy Tsurumi, Damien Maura & Laurence G. Rahme

  2. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Arunava Bandyopadhaya, Amy Tsurumi, Damien Maura & Laurence G. Rahme

  3. Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, 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, 02114, Massachusetts, 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.

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Correspondence to Laurence G. Rahme.

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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.

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Bandyopadhaya, A., Tsurumi, A., Maura, D. et al. A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming. Nat Microbiol 1, 16174 (2016). https://doi.org/10.1038/nmicrobiol.2016.174

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