LeuO regulation of adaptive responses in Vibrio cholerae

LeuO is a LysR-type transcriptional regulator that is conserved among many gram negative enteric pathogens. LeuO is a bifunctional regulator that is capable of both repression and activation of gene targets. The function of LeuO has been characterized in several members of the Enterobacteriaceae where it has been found to be a global regulator of diverse phenotypes, often by functioning as an H-NS antagonist. In this work we sought to characterize LeuO in Vibrio cholerae. RNA sequencing was used to identify LeuO regulated genes, many of which appeared to be involved in environmental adaptation. Interestingly, our results suggested that LeuO did not function as an H-NS antagonist in V. cholerae, but appeared to function redundantly with H-NS at many H-NS regulated promoters. In subsequent experiments, genetic approaches were used to confirm the RNA sequencing studies and to define the function of LeuO in V. cholerae adaptive responses. We found that LeuO was part of a complex regulatory cascade in which the one-component virulence regulator ToxR directly activated leuO expression in response to environmental cues. LeuO then went on to directly regulate genes that contributed to bile resistance, acid tolerance, and cationic antimicrobial peptide resistance. Our collective results suggest a model whereby LeuO contributes to temporal and spatial regulation of adaptive responses during V. cholerae passage through the host gastrointestinal tract