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Pyruvate Protects Pathogenic Spirochetes from H(2)O(2) Killing

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 e...

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Detalles Bibliográficos
Autores principales: Troxell, Bryan, Zhang, Jun-Jie, Bourret, Travis J., Zeng, Melody Yue, Blum, Janice, Gherardini, Frank, Hassan, Hosni M., Yang, X. Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879313/
https://www.ncbi.nlm.nih.gov/pubmed/24392147
http://dx.doi.org/10.1371/journal.pone.0084625
Descripción
Sumario: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 H(2)O(2) scavenger, and provided passive protection to B. burgdorferi and L. interrogans against H(2)O(2). When extracellular pyruvate was absent, both spirochetes were sensitive to a low dose of H(2)O(2) (≈0.6 µM per h) generated by glucose oxidase (GOX). Despite encoding a functional catalase, L. interrogans was more sensitive than B. burgdorferi to H(2)O(2) 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 H(2)O(2) challenge since deletion of the uvrB or the mutS genes enhanced its sensitivity to H(2)O(2) killing; however, the presence of pyruvate fully protected ΔuvrB and ΔmutS from H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) generated by the host antibacterial response generated during infection.