Abstract
Pathogenic Leptospira spp. are the causative agents of the waterborne zoonotic disease leptospirosis. Leptospira are challenged by numerous adverse conditions, including deadly reactive oxygen species (ROS), when infecting their hosts. Withstanding ROS produced by the host innate immunity is an important strategy evolved by pathogenic Leptospira for persisting in and colonizing hosts. In L. interrogans, genes encoding defenses against ROS are repressed by the peroxide stress regulator, PerR. In this study, RNA sequencing was performed to characterize both the L. interrogans response to low and high concentrations of hydrogen peroxide and the PerR regulon. We showed that Leptospira solicit three main peroxidase machineries (catalase, cytochrome C peroxidase and peroxiredoxin) and heme to detoxify oxidants produced during peroxide stress. In addition, canonical molecular chaperones of the heat shock response and DNA repair proteins from the SOS response were required for Leptospira recovering from oxidative damage. Identification of the PerR regulon upon exposure to H2O2 allowed to define the contribution of this regulator in the oxidative stress response. This study has revealed a PerR-independent regulatory network involving other transcriptional regulators, two-component systems and sigma factors as well as non-coding RNAs that putatively orchestrate, in concert with PerR, the oxidative stress response. We have shown that PerR-regulated genes encoding a TonB-dependent transporter and a two-component system (VicKR) are involved in Leptospira tolerance to superoxide. This could represent the first defense mechanism against superoxide in L. interrogans, a bacterium lacking canonical superoxide dismutase. Our findings provide an insight into the mechanisms required by pathogenic Leptospira to overcome oxidative damage during infection-related conditions. This will participate in framing future hypothesis-driven studies to identify and decipher novel virulence mechanisms in this life-threatening pathogen.
Highlights
In order to invade a host and establish persistent colonization, pathogens have evolved a variety of strategies to resist, circumvent, or counteract host defenses
We found that Leptospira solicit peroxidases to detoxify oxidants as well as chaperones of the heat shock response and DNA repair proteins of the SOS response to recover from oxidative damage
Our study indicates that the oxidative stress response is orchestrated by a regulatory network involving peroxide stress regulator (PerR) and other transcriptional regulators, sigma factors, two component systems, and putative non-coding RNAs
Summary
In order to invade a host and establish persistent colonization, pathogens have evolved a variety of strategies to resist, circumvent, or counteract host defenses. The strategies used by pathogenic Leptospira for successful host colonization and virulence are not fully understood. These aerobic Gram-negative bacteria of the spirochetal phylum are the causative agents of leptospirosis, a widespread zoonosis [1]. Rodents are the main reservoir for leptospires as the bacteria asymptomatically colonize the proximal renal tubules of these mammals. Leptospira penetrate mucous membranes or abraded skin, enter the bloodstream and rapidly disseminate to multiple tissues and organs including kidney, liver and lungs. Clinical manifestations range from a mild flu-like febrile state to more severe and fatal cases leading to hemorrhages and multiple organ failure. The lack of efficient tools and techniques for genetic manipulation of Leptospira spp. and their fastidious growth in laboratory conditions have greatly hampered and limited our understanding of their mechanisms of pathogenicity and virulence [4,5]
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