TheStreptococcus agalactiaeLytSR two-component regulatory system promotes vaginal colonisation and virulencein vivo

Abstract

AbstractStreptococcus agalactiae(or Group BStreptococcus, GBS) is a leading cause of neonatal sepsis and meningitis globally. To sense and respond to variations in its environment, GBS possesses multiple two-component regulatory systems (TCSs) such as LytSR. Here, we aimed to investigate the role of LytSR in GBS pathogenicity. We generated an isogeniclytSknockout mutant in a clinical GBS isolate and used a combination of phenotypic in vitro assays and in vivo murine models to investigate the contribution oflytSto the colonisation and invasive properties of GBS. Deletion of thelytSgene in the GBS chromosome resulted in significantly higher survival rates in mice during sepsis, accompanied by reduced bacterial loads in blood, lung, spleen, kidney and brain tissue compared to infection with the wild-type strain. In a mouse model of GBS vaginal colonisation, we also observed that thelytSknockout mutant was cleared more readily from the vaginal tract compared to its wild-type counterpart. Interestingly, lower levels of proinflammatory cytokines were found in the serum of mice infected with thelytSmutant. Our results demonstrate that the LytSR TCS plays a key role in GBS tissue invasion and pathogenesis, and persistence of mucosal colonisation.ImportanceStreptococcus agalactiae (Group B strep, or GBS)is a common commensal of the female urogenital tract and one of WHO’s priority pathogens. The bacterium has evolved mechanisms to adapt and survive in its host, many of which are regulated via two-component signal transduction systems (TCSs), however, the exact contributions of TCSs towards GBS pathogenicity remain largely obscure.We have constructed a TCSlytS-deficient mutant in a CC-17 hypervirulent GBS clinical isolate. Using murine models, we showed that LytSR regulatory system is essential for vaginal colonisation via promoting biofilm production. We also observed thatlytSdeficiency led to significantly attenuated virulence properties and lower levels of proinflammatory cytokines in blood. Our findings are of significant importance in that they unveil a previously unreported role for LytSR in GBS and pave the way towards a better understanding of its ability to transition from an innocuous commensal to a deadly pathogen.