title: Pyruvate protects pathogenic spirochetes from H2O2 killing.
abstract: Pathogenic spirochetes cause clinically relevant diseases in humans and animals, such as Lyme disease and leptospirosis. The causative agent of Lyme disease, Borrelia burgdorferi, and the causative agent of leptospirosis, Leptospria interrogans, encounter reactive oxygen species (ROS) during their enzootic cycles. This report demonstrated that physiologically relevant concentrations of pyruvate, a potent H2O2 scavenger, and provided passive protection to B. burgdorferi and L. interrogans against H2O2. When extracellular pyruvate was absent, both spirochetes were sensitive to a low dose of H2O2 (≈0.6 µM per h) generated by glucose oxidase (GOX). Despite encoding a functional catalase, L. interrogans was more sensitive than B. burgdorferi to H2O2 generated by GOX, which may be due to the inherent resistance of B. burgdorferi because of the virtual absence of intracellular iron. In B. burgdorferi, the nucleotide excision repair (NER) and the DNA mismatch repair (MMR) pathways were important for survival during H2O2 challenge since deletion of the uvrB or the mutS genes enhanced its sensitivity to H2O2 killing; however, the presence of pyruvate fully protected ΔuvrB and ΔmutS from H2O2 killing further demonstrating the importance of pyruvate in protection. These findings demonstrated that pyruvate, in addition to its classical role in central carbon metabolism, serves as an important H2O2 scavenger for pathogenic spirochetes. Furthermore, pyruvate reduced ROS generated by human neutrophils in response to the Toll-like receptor 2 (TLR2) agonist zymosan. In addition, pyruvate reduced neutrophil-derived ROS in response to B. burgdorferi, which also activates host expression through TLR2 signaling. Thus, pathogenic spirochetes may exploit the metabolite pyruvate, present in blood and tissues, to survive H2O2 generated by the host antibacterial response generated during infection.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Troxell
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Biology, University of Nebraska Kearney, Nebraska, United States of America.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Bourret
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Melody Yue
authors.initials: MY
authors.lastname: Zeng
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Janice
authors.initials: J
authors.lastname: Blum
authors.affiliation: Laboratory of Zoonotic Pathogens, National Institute of Allergy and Infectious Diseases, National Institute of Health, Hamilton, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Gherardini
authors.affiliation: Department of Microbiology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Hosni M
authors.initials: HM
authors.lastname: Hassan
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: X Frank
authors.initials: XF
authors.lastname: Yang
mesh_terms: D000085:Acetates / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D025065:Borrelia burgdorferi / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D017353:Gene Deletion; D005949:Glucose Oxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology; D018384:Oxidative Stress / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013144:Spirochaetales / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000085:Acetates; D001426:Bacterial Proteins; D017382:Reactive Oxygen Species; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D051719:MutS DNA Mismatch-Binding Protein