Clinical epigenetics and multidrug-resistant bacterial infections: host remodelling in critical illness

Epigenetics. 2020 Oct;15(10):1021-1034. doi: 10.1080/15592294.2020.1748918. Epub 2020 Apr 14.

Abstract

The inappropriate use of antibiotics in man is driving to insurgence of pathogenic bacteria resistant to multiple drugs (MDR) representing a challenge in critical illness. The interaction of MDR bacteria with host cells can guide molecular perturbations of host transcriptional programmes involving epigenetic-sensitive mechanisms, mainly DNA methylation, histone modifications, and non-coding RNAs leading to pathogen survival. Clinical evidence of epigenetic manipulation from MDR bacteria mainly arises from Mycobacterium tuberculosis as well as Helicobacter pylori, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Legionella pneumophila infection suggesting possible biomarkers of disease. For example, DNA hypermethylation of E-cadherin (CDH1), upstream transcription factor 1/2 (USF1/2), WW domain containing oxidoreductase (WWOX), and mutL homolog 1 (MLH1) genes in gastric mucosa is correlated with malignancy suggesting useful biomarkers of early disease state. Moreover, upregulated circulating miR-361-5p, miR-889, miR-576-3p may be useful biomarkers to discriminate tuberculosis patients. Moreover, Listeria monocytogenes can indirectly induce H3 hyperacetylation leading to inflammation in human endothelial cells whereas Pseudomonas aeruginosa excretes QS 2-AA to directly induce H3 deacetylation leading to bacterial persistence in human monocytes. Remarkably, epigenetic-sensitive drugs may aid to counteract MDR in clinical setting. Trichostatin A, a histone deacetyltransferase inhibitor (HDACi), leads to AMP β-defensin 2 (HBD2) gene up-regulation in human epithelial cells suggesting a useful 'epi-therapy' for Escherichia coli-induced intestinal diseases. We update on the most current clinical studies focusing on epigenetic changes involved in bacterial-host interactions and their putative role as biomarkers or drug targets to improve precision medicine and personalized therapy in critical illness and transplantation setting.

Keywords: Bacterial infections; biomarkers; epidrugs; epigenetics; personalized therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bacterial Infections / drug therapy
  • Bacterial Infections / genetics*
  • Bacterial Infections / microbiology
  • Critical Illness
  • Drug Resistance, Multiple, Bacterial*
  • Epigenome*
  • Epigenomics / methods*
  • Host-Pathogen Interactions
  • Humans
  • Precision Medicine / methods*

Grants and funding

This work was supported by PRIN2017F8ZB89 from Italian Ministry of Research (PI Prof Napoli). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Giuditta Benincasa is a PhD student of Translational Medicine awarded ESC Congress 2019 and she is supported by Educational Grant from the University of Campania, Naples, Italy.