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The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans

View ORCID ProfileAndré A. Grassmann, Crispin Zavala-Alvarado, View ORCID ProfileEverton B. Bettin, Mathieu Picardeau, Nadia Benaroudj, View ORCID ProfileMelissa J. Caimano
doi: https://doi.org/10.1101/2020.11.05.369660
André A. Grassmann
1Department of Medicine, University of Connecticut Health, Farmington, Connecticut, USA
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Crispin Zavala-Alvarado
2Unité de Biologie des Spirochètes, Department of Microbiology, Institut Pasteur, Paris, France
3Université de Paris, Sorbonne Paris Cité, Communauté d’universités et d’établissements (COMUE), Bio Sorbonne Paris Cité (BioSPC), Paris, France
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Everton B. Bettin
1Department of Medicine, University of Connecticut Health, Farmington, Connecticut, USA
4Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sol, Brazil
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Mathieu Picardeau
2Unité de Biologie des Spirochètes, Department of Microbiology, Institut Pasteur, Paris, France
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Nadia Benaroudj
2Unité de Biologie des Spirochètes, Department of Microbiology, Institut Pasteur, Paris, France
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Melissa J. Caimano
1Department of Medicine, University of Connecticut Health, Farmington, Connecticut, USA
5Department of Pediatrics and 6Molecular Biology and Biophysics, University of Connecticut Health, Farmington, Connecticut, USA
6Department of Molecular Biology and Biophysics, University of Connecticut Health, Farmington, Connecticut, USA
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  • For correspondence: mcaima@uchc.edu
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Abstract

Leptospira interrogans, the causative agent of most cases of human leptospirosis, must respond to myriad environmental signals during its free-living and pathogenic lifestyles. Previously, we compared L. interrogans cultivated in vitro and in vivo using a dialysis membrane chamber (DMC) peritoneal implant model. From these studies emerged the importance of genes encoding the Peroxide responsive regulators PerRA and PerRB. First described in in Bacillus subtilis, PerRs are widespread in Gram-negative and -positive bacteria, where regulate the expression of gene products involved in detoxification of reactive oxygen species and virulence. Using perRA and perRB single and double mutants, we establish that L. interrogans requires at least one functional PerR for infectivity and renal colonization in a reservoir host. Our finding that the perRA/B double mutant survives at wild-type levels in DMCs is noteworthy as it demonstrates that the loss of virulence is not due to a metabolic lesion (i.e., metal starvation) but instead reflects dysregulation of virulence-related gene products. Comparative RNA-Seq analyses of perRA, perRB and perRA/B mutants cultivated within DMCs identified 106 genes that are dysregulated in the double mutant, including ligA, ligB and lvrA/B sensory histidine kinases. Decreased expression of LigA and LigB in the perRA/B mutant was not due to loss of LvrAB signaling. The majority of genes in the perRA and perRB single and double mutant DMC regulons were differentially expressed only in vivo, highlighting the importance of host signals for regulating gene expression in L. interrogans. Importantly, the PerRA, PerRB and PerRA/B DMC regulons each contain multiple genes related to environmental sensing and/or transcriptional regulation. Collectively, our data suggest that PerRA and PerRB are part of a complex regulatory network that promotes host adaptation by L. interrogans within mammals.

Author Summary Leptospirosis is a neglected tropical disease with a worldwide distribution. Globally, ~1 million cases and ~60,000 deaths are reported each year. The majority of cases of human leptospirosis are associated with Leptospira interrogans. Infection begins when a naïve reservoir (or incidental) host comes into direct or indirect contact with urine from an infected reservoir host. While infection in reservoir hosts, including rats and mice, is generally asymptomatic, incidental hosts, including humans, may develop clinical symptoms ranging from mild flu-like illness to fulminant disease. The gene products required by leptospires for infection remain poorly understood. Herein, we establish that the FUR family regulators PerRA and PerRB function in parallel, contributing to infectivity and renal colonization in mice. By comparative transcriptomics, we identified >100 genes that were dysregulated in the perRA/B double mutant cultivated in rat peritoneal cavities, including the virulence determinants LigA and LigB. Importantly, the PerRA, PerRB and PerRA/B DMC regulons contain multiple genes related to environmental sensing and/or transcriptional regulation. Our data suggest that PerRA and PerRB are part of a complex regulatory network that promotes host adaptation by L. interrogans within mammals.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 02, 2021.
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The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans
André A. Grassmann, Crispin Zavala-Alvarado, Everton B. Bettin, Mathieu Picardeau, Nadia Benaroudj, Melissa J. Caimano
bioRxiv 2020.11.05.369660; doi: https://doi.org/10.1101/2020.11.05.369660
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The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans
André A. Grassmann, Crispin Zavala-Alvarado, Everton B. Bettin, Mathieu Picardeau, Nadia Benaroudj, Melissa J. Caimano
bioRxiv 2020.11.05.369660; doi: https://doi.org/10.1101/2020.11.05.369660

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