The adaptive transcriptional response of pathogenicLeptospirato peroxide reveals new defenses against infection-related oxidative stress
Authors: Zavala-Alvarado Crispin , Sismeiro Odile , Legendre Rachel , Varet Hugo , Bussotti Giovanni , Bayram Jan , Huete Samuel Garcia , Rey Guillaume , Coppée Jean-Yves , Picardeau Mathieu , Benaroudj Nadia 
Published: April 2020

PathogenicLeptospiraspp. are the causative agents of the waterborne zoonotic disease leptospirosis. During infection,Leptospiraare confronted with dramatic adverse environmental changes such as deadly reactive oxygen species (ROS). Withstanding ROS produced by the host innate immunity is an important strategy evolved by pathogenicLeptospirafor persisting in and colonizing hosts. InL. interrogans, genes encoding defenses against ROS are repressed by the peroxide stress regulator, PerR. In this study, RNA sequencing was performed to characterize both theL. interrogansadaptive response to low and high concentrations of hydrogen peroxide and the PerR regulon. We showed thatLeptospirasolicit three main peroxidase machineries (catalase, cytochrome C peroxidase and peroxiredoxin) and heme to detoxify oxidants produced during a peroxide stress. In addition, canonical molecular chaperones of the heat shock response and DNA repair proteins from the SOS response were required forLeptospirarecovering from oxidative damages. Determining the PerR regulon allowed to identify the PerR-dependent mechanisms of the peroxide adaptive response and 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, this adaptive response. In addition, we have identified other PerR-regulated genes encoding a TonB-dependent transport system, a lipoprotein (LipL48) and a two-component system (VicKR) involved inLeptospiratolerance to superoxide and that could represent the first defense mechanism against superoxide inL. interrogans, a bacterium lacking canonical superoxide dismutase. Our findings provide a comprehensive insight into the mechanisms required by pathogenicLeptospirato overcome infection-related oxidants during the arm race with a host. This will participate in framing future hypothesis-driven studies to identify and decipher novel virulence mechanisms in this life-threatening pathogen.

Author summary

Leptospirosis is a zoonotic infectious disease responsible for over one million of severe cases and 60 000 fatalities annually worldwide. This neglected and emerging disease has a worldwide distribution, but it mostly affects populations from developing countries in sub-tropical areas. The causative agents of leptospirosis are pathogenic bacterialLeptospiraspp. There is a considerable deficit in our knowledge of these atypical bacteria, including their virulence mechanisms. During infection,Leptospiraare confronted with the deadly oxidants produced by the host tissues and immune response. Here, we have identified the cellular factors necessary forLeptospirato overcome the oxidative stress response. We found thatLeptospirasolicit 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. Moreover, our study indicates that adaptation to oxidative stress is orchestrated by a regulatory network involving PerR and other transcriptional regulators, sigma factors, two component systems, and putative non-coding RNAs. These findings provide a comprehensive insight into the mechanisms required by pathogenicLeptospirato tolerate infection-related oxidants, helping identify novel virulence factors, developing new therapeutic targets and vaccines against leptospirosis.