mcr-1 Gene Expression Modulates the Inflammatory Response of Human Macrophages to Escherichia coli

Giorgio Mattiuz; Sabrina Nicolò; Alberto Antonelli; Tommaso Giani; Ilaria Baccani; Antonio Cannatelli; Ann Maria Clemente; Giuseppe Castronovo; Michele Tanturli; Federico Cozzolino; Gian Maria Rossolini; Maria Gabriella Torcia

doi:10.1128/IAI.00018-20

mcr-1 Gene Expression Modulates the Inflammatory Response of Human Macrophages to Escherichia coli

Infect Immun. 2020 Jul 21;88(8):e00018-20. doi: 10.1128/IAI.00018-20. Print 2020 Jul 21.

Authors

Affiliations

¹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
² Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy [email protected].
³ Clinical Microbiology and Virology Unit, Careggi University Hospital, Florence, Italy.
⁴ Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁵ Department of Clinical, Experimental and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

Abstract

MCR-1 is a plasmid-encoded phosphoethanolamine transferase able to modify the lipid A structure. It confers resistance to colistin and was isolated from human, animal, and environmental strains of Enterobacteriaceae, raising serious global health concerns. In this paper, we used recombinant mcr-1-expressing Escherichia coli to study the impact of MCR-1 products on E. coli-induced activation of inflammatory pathways in activated THP-1 cells, which was used as a model of human macrophages. We found that infection with recombinant mcr-1-expressing E. coli significantly modulated p38-MAPK and Jun N-terminal protein kinase (JNK) activation and pNF-κB nuclear translocation as well as the expression of genes for the relevant proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and IL-1β compared with mcr-1-negative strains. Caspase-1 activity and IL-1β secretion were significantly less activated by mcr-1-positive E. coli strains than the mcr-1-negative parental strain. Similar results were obtained with clinical isolates of mcr-1-positive E. coli, suggesting that, in addition to colistin resistance, the expression of mcr-1 allows the escape of early host innate defenses and may promote bacterial survival.

Keywords: MCR-1; cytokines; inflammation; macrophages.

Publication types

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

MeSH terms

Active Transport, Cell Nucleus / drug effects
Caspase 1 / genetics
Caspase 1 / immunology
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Nucleus / microbiology
Cytoplasm / drug effects
Cytoplasm / metabolism
Cytoplasm / microbiology
Escherichia coli / genetics*
Escherichia coli / immunology
Escherichia coli Proteins / genetics*
Escherichia coli Proteins / immunology
Gene Expression Regulation / immunology*
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Humans
Inflammation
Interleukin-12 / genetics
Interleukin-12 / immunology
Interleukin-1beta / genetics
Interleukin-1beta / immunology
MAP Kinase Kinase 4 / genetics*
MAP Kinase Kinase 4 / immunology
Microbial Viability
NF-kappa B / genetics*
NF-kappa B / immunology
Phagocytosis / drug effects
Phagocytosis / genetics
Signal Transduction
THP-1 Cells
Tetradecanoylphorbol Acetate / pharmacology
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / immunology
p38 Mitogen-Activated Protein Kinases / genetics*
p38 Mitogen-Activated Protein Kinases / immunology

Substances

Escherichia coli Proteins
IL1B protein, human
Interleukin-1beta
MCR-1 protein, E coli
NF-kappa B
Tumor Necrosis Factor-alpha
Interleukin-12
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase 4
Caspase 1
Tetradecanoylphorbol Acetate