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 (1) , Crispin Zavala-Alvarado (2, 3) , Everton B. Bettin (1, 4) , Mathieu Picardeau (2) , Nadia Benaroudj (2) , Melissa J. Caimano (1)

1 UCONN - University of Connecticut
2 Biologie des Spirochètes / Biology of Spirochetes
3 ED562 - BioSPC - École Doctorale Bio Sorbonne Paris Cité [Paris]
4 UFPel - Universidade Federal de Pelotas = Federal University of Pelotas

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.

Domaines: Microbiologie et Parasitologie

André A. Grassmann, Crispin Zavala-Alvarado, Everton B. Bettin, Mathieu Picardeau, Nadia Benaroudj, et al.. The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans. PLoS Pathogens, 2021, 17 (12), pp.e1009078. ⟨10.1371/journal.ppat.1009078⟩. ⟨pasteur-03697610⟩