title: Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.
abstract: Streptococcus agalactiae (Group B Streptococcus, GBS) is a frequent commensal organism of the vaginal tract of healthy women. However, GBS can transition to a pathogen in susceptible hosts, but host and microbial factors that contribute to this conversion are not well understood. GBS CovR/S (CsrR/S) is a two component regulatory system that regulates key virulence elements including adherence and toxin production. We performed global transcription profiling of human vaginal epithelial cells exposed to WT, CovR deficient, and toxin deficient strains, and observed that insufficient regulation by CovR and subsequent increased toxin production results in a drastic increase in host inflammatory responses, particularly in cytokine signalling pathways promoted by IL-8 and CXCL2. Additionally, we observed that CovR regulation impacts epithelial cell attachment and intracellular invasion. In our mouse model of GBS vaginal colonization, we further demonstrated that CovR regulation promotes vaginal persistence, as infection with a CovR deficient strainresulted in a heightened host immune response as measured by cytokine production and neutrophil activation. Using CXCr2 KO mice, we determined that this immune alteration occurs, at least in part, via signalling through the CXCL2 receptor. Taken together, we conclude that CovR is an important regulator of GBS vaginal colonization and loss of this regulatory function may contribute to the inflammatory havoc seen during the course of infection.
authors.affiliation: Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Patras
authors.forename: Nai-Yu
authors.initials: NY
authors.lastname: Wang
authors.forename: Erin M
authors.initials: EM
authors.lastname: Fletcher
authors.forename: Courtney K
authors.initials: CK
authors.lastname: Cavaco
authors.forename: Alyssa
authors.initials: A
authors.lastname: Jimenez
authors.forename: Mansi
authors.initials: M
authors.lastname: Garg
authors.forename: Joshua
authors.initials: J
authors.lastname: Fierer
authors.forename: Tamsin R
authors.initials: TR
authors.lastname: Sheen
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013292:Streptococcus agalactiae / Q000276:immunology* / Q000472:pathogenicity*; D014621:Vagina / Q000276:immunology* / Q000382:microbiology*
chemical_list: D001426:Bacterial Proteins; D023063:Receptors, Interleukin-8B; D012097:Repressor Proteins