4-hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen
- University of Washington, United States
Abstract
Pathogens encounter numerous antimicrobial responses during infection, including the reactive oxygen species (ROS) burst. ROS-mediated oxidation of host membrane poly-unsaturated fatty acids (PUFAs) generates the toxic alpha-beta carbonyl 4-hydroxy-2-nonenal (4-HNE). Though studied extensively in the context of sterile inflammation, research into 4-HNE's role during infection remains limited. Here we found that 4-HNE is generated during bacterial infection, that it impacts growth and survival in a range of bacteria, and that the intracellular pathogen Listeria monocytogenes induces many genes in response to 4-HNE exposure. A component of the L. monocytogenes 4-HNE response is the expression of the genes lmo0103 and lmo0613, deemed rha1 and rha2 (reductase of host alkenals), respectively, which code for two NADPH-dependent oxidoreductases that convert 4-HNE to the product 4-hydroxynonanal (4-HNA). Loss of these genes had no impact on L. monocytogenes bacterial burdens during murine or tissue culture infection. However, heterologous expression of rha1/2 in Bacillus subtilis significantly increased bacterial resistance to 4-HNE in vitro and promoted bacterial survival following phagocytosis by murine macrophages in an ROS dependent manner. Thus, Rha1 and Rha2 are not necessary for 4-HNE resistance in L. monocytogenes but are sufficient to confer resistance to an otherwise sensitive organism in vitro and in host cells. Our work demonstrates that 4-HNE is a previously unappreciated component of ROS-mediated toxicity encountered by bacteria within eukaryotic hosts.
Data availability
All RNA sequencing data have been deposited to the GEO and are accessible using accession number GSE150188.
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4-hydroxy-2-nonenal (4-HNE) induced transcriptional changes in Listeria monocytogenesNCBI Gene Expression Omnibus, GSE150188.
Article and author information
Author details
Adelle P McFarland
Funding
National Institute of General Medical Sciences (PHS NRSA T32GM007270)
- Hannah Tabakh
- Alex J Pollock
National Science Foundation (DGE-1256082)
- Adelle P McFarland
National Institute of Allergy and Infectious Diseases (R01AI116669)
- Joshua J Woodward
National Institute of Allergy and Infectious Diseases (R21AI127833)
- Joshua J Woodward
National Cancer Institute (1F30CA239659-01A1)
- Shivam A Zaver
National Institute of Allergy and Infectious Diseases (5T32AI055396)
- Rochelle C Glover
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kim Orth, HHMI/University of Texas Southwestern Medical Center, United States
Ethics
Animal experimentation: All experiments involving mice were performed in compliance with guidelines set by the American Association for Laboratory Animal Science (AALAS) and were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Washington under protocol #4289-01.
Version history
- Received: May 25, 2020
- Accepted: May 5, 2021
- Accepted Manuscript published: May 6, 2021 (version 1)
- Version of Record published: May 27, 2021 (version 2)
Copyright
© 2021, Tabakh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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4-hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen
eLife 10:e59295.
https://doi.org/10.7554/eLife.59295
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