4-hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen

• Published in: eLife Vol. 10
• Main Authors: Tabakh, Hannah, McFarland, Adelle P, Thomason, Maureen K, Pollock, Alex J, Glover, Rochelle C, Zaver, Shivam A, Woodward, Joshua J
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06.05.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: 4-HNE; Amino acids; Antibodies; Antimicrobial agents; Bacteria; Bacterial infections; bacterial pathogenesis; Cell culture; Drug resistance; Enzymes; Genetic aspects; Health aspects; Infection; Infections; Inflammation; Intracellular; Listeria monocytogenes; Macrophages; Microbiology and Infectious Disease; Oxidases; Oxidation; Pathogens; Phagocytosis; Polyunsaturated fatty acids; Proteins; Reactive oxygen species; Scientific equipment and supplies industry; Spleen; Tissue culture; Toxicity; Unsaturated fatty acids; United States; B. subtilis; microbiology; mouse; infectious disease; E. coli
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.59295

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 induces many genes in response to 4-HNE exposure. A component of the 4-HNE response is the expression of the genes and deemed and (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 bacterial burdens during murine or tissue culture infection. However, heterologous expression of in significantly increased bacterial resistance to 4-HNE 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 but are sufficient to confer resistance to an otherwise sensitive organism 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.