TsrA Regulates Virulence and Intestinal Colonization in Vibrio cholerae.

Cory D Dupai,Ashley L Cunningham,Aaron R Conrado,Bryan W Davies,Claus O Wilke,Sarah E F D’Orazio

doi:10.1128/msphere.01014-20

Abstract

Pathogenic strains of Vibrio cholerae require careful regulation of horizontally acquired virulence factors that are largely located on horizontally acquired genomic islands (HAIs). While TsrA, a Vibrionaceae-specific protein, is known to regulate the critical HAI virulence genes toxT and ctxA, its broader function throughout the genome is unknown. Here, we find that deletion of tsrA results in genomewide expression patterns that heavily correlate with those seen upon deletion of hns, a widely conserved bacterial protein that regulates V. cholerae virulence. This correlation is particularly strong for loci on HAIs, where all differentially expressed loci in the ΔtsrA mutant are also differentially expressed in the Δhns mutant. Correlation between TsrA and H-NS function extends to in vivo virulence phenotypes where deletion of tsrA compensates for the loss of ToxR activity in V. cholerae and promotes wild-type levels of mouse intestinal colonization. All in all, we find that TsrA broadly controls V. cholerae infectivity via repression of key HAI virulence genes and many other targets in the H-NS regulon.IMPORTANCE Cholera is a potentially lethal disease that is endemic in much of the developing world. Vibrio cholerae, the bacterium underlying the disease, infects humans utilizing proteins encoded on horizontally acquired genetic material. Here, we provide evidence that TsrA, a Vibrionaceae-specific protein, plays a critical role in regulating these genetic elements and is essential for V. cholerae virulence in a mouse intestinal model.

Highlights

Pathogenic strains of Vibrio cholerae require careful regulation of horizontally acquired virulence factors that are largely located on horizontally acquired genomic islands (HAIs)
While multiple HAIs play some role in virulence [2, 5,6,7,8,9,10,11], genes on V. cholerae pathogenicity island 1 (VPI-1) and the cholera toxin (CTX) prophage are most involved with the major virulence pathway, the ToxR regulon [4, 12]
TsrA regulates V. cholerae gene expression of ctxA and toxT and that TsrA is structurally similar to the oligomerization domain of histone-like nucleoid structuring protein (H-NS) [34]

Summary

Introduction

Pathogenic strains of Vibrio cholerae require careful regulation of horizontally acquired virulence factors that are largely located on horizontally acquired genomic islands (HAIs). We find that deletion of tsrA results in genomewide expression patterns that heavily correlate with those seen upon deletion of hns, a widely conserved bacterial protein that regulates V. cholerae virulence. This correlation is strong for loci on HAIs, where all differentially expressed loci in the DtsrA mutant are differentially expressed in the Dhns mutant. Several factors on the progenitor genome and horizontally acquired genetic islands (HAIs) [1,2,3,4] act in concert to control V. cholerae virulence gene expression. TsrA is a Vibrionaceae-specific protein that is by far most common in the genomes of organisms within the Vibrio genus, as determined via BLAST-based [33] protein

Methods

Results

Conclusion