Pyruvate protects pathogenic spirochetes from H2O2 killing

• Published in: PloS one 2014, Vol.9 (1), p.e84625
• Main Authors: Troxell, Bryan, Zhang, Jun-Jie, Bourret, Travis J, Zeng, Melody Yue, Blum, Janice, Gherardini, Frank, Hassan, Hosni M, Yang, X Frank
• Format: Article
• Language: English
• Subjects: Acetates - metabolism; Arachnids; Arthritis; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biology; Borrelia burgdorferi; Borrelia burgdorferi - drug effects; Borrelia burgdorferi - genetics; Borrelia burgdorferi - metabolism; Carbon; Catalase; Deoxyribonucleic acid; DNA; DNA repair; DNA Repair - drug effects; Dosage; Gene Deletion; Gene expression; Glucose oxidase; Glucose Oxidase - metabolism; Human behavior; Humans; Hydrogen peroxide; Hydrogen Peroxide - toxicity; Immunology; Infections; Iron; Killing; Leptospira interrogans; Leptospirosis; Leukocytes (neutrophilic); Lyme disease; Mammals; Medicine; Metabolism; Metabolites; Mismatch repair; MutS DNA Mismatch-Binding Protein - genetics; MutS DNA Mismatch-Binding Protein - metabolism; Neutrophils; Neutrophils - metabolism; Neutrophils - microbiology; Nitric oxide; Nucleotide excision repair; Oxidative Stress - drug effects; Oxygen; Pathology; Peromyscus leucopus; Pyruvic acid; Pyruvic Acid - metabolism; Pyruvic Acid - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Repair; Rodents; Sensitivity enhancement; Signaling; Spirochaetales - drug effects; Spirochaetales - genetics; Spirochaetales - metabolism; Spirochetes; Tissues; TLR2 protein; Toll-like receptors; Vector-borne diseases; Zoonoses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084625

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.