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The transcriptional response of pathogenic Leptospira to peroxide reveals new defenses against infection-related oxidative stress.

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.

SUBMITTER: Zavala-Alvarado C

PROVIDER: S-EPMC7567364 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The transcriptional response of pathogenic Leptospira to peroxide reveals new defenses against infection-related oxidative stress.

Zavala-Alvarado Crispin C Sismeiro Odile O Legendre Rachel R Varet Hugo H Bussotti Giovanni G Bayram Jan J G Huete Samuel S Rey Guillaume G Coppée Jean-Yves JY Picardeau Mathieu M Benaroudj Nadia N

PLoS pathogens 20201006 10

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 ...[more]

PMID: 33021995

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Project description:Pathogenic Leptospira are the causative agents of leptospirosis, the most widespread zoonotic infectious disease. Leptospirosis is a potentially severe and life-threatening emerging disease with highest burden in sub-tropical areas and impoverished populations. Mechanisms allowing pathogenic Leptospira to survive inside a host and induce acute leptospirosis are not fully understood. The ability to resist deadly oxidants produced by the host during infection is pivotal for Leptospira virulence. We have previously shown that genes encoding defenses against oxidants in L. interrogans are repressed by PerRA (encoded by LIMLP_10155), a peroxide stress regulator of the Fur family. In this study, we describe the identification and characterization of another putative PerR-like regulator (LIMLP_05620) in L. interrogans. Protein sequence and phylogenetic analyses indicated that LIMLP_05620 displayed all the canonical PerR amino acid residues and is restricted to pathogenic Leptospira clades. We therefore named this PerR-like regulator PerRB. In L. interrogans, the PerRB regulon is distinct from that of PerRA. While a perRA mutant had a greater tolerance to peroxide, inactivating perRB led to a higher tolerance to superoxide, suggesting that these two regulators have a distinct function in the adaptation of L. interrogans to oxidative stress. The concomitant inactivation of perRA and perRB resulted in a higher tolerance to both peroxide and superoxide and, unlike the single mutants, a double perRAperRB mutant was avirulent. Interestingly, this correlated with major changes in gene and non-coding RNA expression. Notably, several virulence-associated genes (clpB, ligA/B, and lvrAB) were repressed. By obtaining a double mutant in a pathogenic Leptospira strain, our study has uncovered an interplay of two PerRs in the adaptation of Leptospira to oxidative stress with a putative role in virulence and pathogenicity, most likely through the transcriptional control of a complex regulatory network.

Project description:Characterization of the human microbiota is providing new insightsinto the complexity of host–parasite–bacterium relationships. Amoebiasis (an intestinal infection affecting a large proportion of the population in many countries worldwide) is caused by the amoebic parasite Entamoeba histolytica. During amoebiasis, the parasite encounters several types of stress as a result of the host’s response to infection. Given that E. histolytica phagocytises bacteria in the intestinal lumen, we hypothesized that enteric bacteria can influence the course of an amoebic infection. Hence, we used live Escherichia coli O55 as a pertinent model of the bacterial community’s contribution to amoebic responses during host- induced stress. By measuring amoebic survival, we found that live E. coli protected E. histolytica against oxidative stress (OS) but not against nitrosative stress. E. coli– associated protection is correlated with massive transcriptionalchanges in amoebic genes acquired through lateral transfer from the bacterial kingdom, including genes coding for proteinscontaining leucine-rich repeat (LRR) motifs. The transcriptome profile triggered by OS and E. coli was also observed with other enteric bacteria, including pathogens and non-pathogens. In contrast, exposure to a probiotic resulted in a different transcriptome profile. The present study shows that OS and live bacteria together modulate 84 of E. histolytica’s 137 LRR protein genes. The LRR proteins are involvedin protein-ligand and protein-protein interactions – especially in proteins that interact with bacteria as part of the innate immune response in mammals and plants, such as Toll-like receptors. The structural and functional homology of LRRs and TLRs identified here suggest that despite its old age in evolutionary terms, the protozoan E. histolytica displays key characteristics of higher eukaryotes’ innate immune systems. We conclude that components of innate immunity existed in the common ancestor of plants and animals

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The transcriptional response of pathogenic Leptospira to peroxide reveals new defenses against infection-related oxidative stress.

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The transcriptional response of pathogenic Leptospira to peroxide reveals new defenses against infection-related oxidative stress.

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