Up to 50% of humans experience urinary tract infections (UTI) during their life. Group B Streptococcus (GBS; Streptococcus agalactiae) can colonize the urinary tract and cause UTI in adults, the elderly and immunocompromised individuals. The mechanisms and virulence factors that influence the ability of GBS to cause UTI are not fully elucidated. The CovRS two-component global response regulator controls the expression of hundreds of genes in GBS, and comprises the response receiver CovS and the DNA binding CovR protein. Regulatory targets of CovR include cytotoxins, adhesins and capsular polysaccharide. Prior studies have associated mutation in covR with hyper-virulence, partly due to the overexpression of the GBS β-hemolysin/cytolysin (β-h/c).
We show that CovR enhances the ability of GBS to cause acute UTI using both in vivo and in vitro UTI models. Mutation in covR perturbed the ability of GBS to colonize the bladder and urine in a mouse UTI model, and reduced the levels of adherence towards and invasion of human bladder uroepithelial cells. covR mutation also caused increased β-h/c activity, death of uroepithelial cells and caspase-3 activation. Analysis of the immune responses produced during our in vitro and in vivo experiments showed altered levels of a number of pro-inflammatory cytokines and chemokines, including IL-6, IL-17A, GM-CSF and KC/IL-8, and these responses occurred in a covR-dependent manner. Examination of several known CovR-regulated virulence factors revealed that CovR repression of the adhesin gene hvgA partly explains the complex role of CovR in promoting UTI.
Collectively, these data highlight CovR as a central regulator of GBS virulence factors that influence the pathogenesis of UTI. We conclude the mechanisms underlying CovR-dependent phenotypes in UTI are complex and multifactorial due to the pleiotropic nature of the CovRS virulence regulator system in GBS.