Dataset Information

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.

SUBMITTER: Patras KA

PROVIDER: S-EPMC3657335 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.

Patras Kathryn A KA Wang Nai-Yu NY Fletcher Erin M EM Cavaco Courtney K CK Jimenez Alyssa A Garg Mansi M Fierer Joshua J Sheen Tamsin R TR Rajagopal Lakshmi L Doran Kelly S KS

Cellular microbiology 20130130 7

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 expo ...[more]

PMID: 23298320

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Project description:Group B Streptococcus (GBS) colonizes the vaginal mucosa of a significant percentage of healthy women and is a leading cause of neonatal bacterial infections. Currently, pregnant women are screened in the last month of pregnancy, and GBS-positive women are given antibiotics during parturition to prevent bacterial transmission to the neonate. Recently, human milk oligosaccharides (HMOs) isolated from breastmilk were found to inhibit GBS growth and biofilm formation in vitro, and women that make certain HMOs are less likely to be vaginally colonized with GBS. Using in vitro human vaginal epithelial cells and a murine vaginal colonization model, we tested the impact of HMO treatment on GBS burdens and the composition of the endogenous microbiota by 16S rRNA amplicon sequencing. HMO treatment reduced GBS vaginal burdens in vivo with minimal alterations to the vaginal microbiota. HMOs displayed potent inhibitory activity against GBS in vitro, but HMO pretreatment did not alter adherence of GBS or the probiotic Lactobacillus rhamnosus to human vaginal epithelial cells. In addition, disruption of a putative GBS glycosyltransferase (Δsan_0913) rendered the bacterium largely resistant to HMO inhibition in vitro and in vivo but did not compromise its adherence, colonization, or biofilm formation in the absence of HMOs. We conclude that HMOs are a promising therapeutic bioactive to limit GBS vaginal colonization with minimal impacts on the vaginal microenvironment. IMPORTANCE During pregnancy, GBS ascension into the uterus can cause fetal infection or preterm birth. In addition, GBS exposure during labor creates a risk of serious disease in the vulnerable newborn and mother postpartum. Current recommended prophylaxis consists of administering broad-spectrum antibiotics to GBS-positive mothers during labor. Although antibiotics have significantly reduced GBS neonatal disease, there are several unintended consequences, including altered neonatal gut bacteria and increased risk for other types of infection. Innovative preventions displaying more targeted antimicrobial activity, while leaving the maternal microbiota intact, are thus appealing. Using a mouse model, we found that human milk oligosaccharides (HMOs) reduce GBS burdens without perturbing the vaginal microbiota. We conclude that HMOs are a promising alternative to antibiotics to reduce GBS neonatal disease.

Project description:Group B Streptococcus (GBS) colonizes the female reproductive tract (FRT) and causes adverse pregnancy outcomes and invasive disease following vertical transmission to the fetus or newborn. Despite this major public health burden, the mechanisms of GBS FRT colonization are understudied. A recent transposon sequencing screen identified GBS factors contributing to vaginal colonization and ascending spread, including a putative DNA-cytosine methyltransferase (Dcm). We constructed a Δdcm deletion strain and confirmed that dcm contributes to murine FRT colonization. Investigation of the evolutionary origin of the dcm gene reveals that it is widely distributed across GBS and is encoded as part of a prophage genome that displays evidence of horizontal transfer between GBS strains. We further show that Dcm contributes to 5mC methylation and global regulation of genes involved in carbohydrate metabolism, transcription regulation, and known adhesins and metabolic factors involved in GBS colonization. Interestingly, GBS genes that are induced in the presence of the highly glycosylated vaginal mucin MUC5B were significantly downregulated in the ∆dcm mutant. Furthermore, the ∆dcm mutant exhibited reduced binding to immobilized mucin and was attenuated in its ability to grow on numerous carbon sources including the carbohydrates found on mucins. While the ∆dcm mutant displayed enhanced clearance from the FRT in wild-type mice, there was no significant difference in MUC5B -/- mice, indicating that Dcm-mediated regulation requires MUC5B to promote GBS colonization. This is the first report to characterize the impact of a DNA methyltransferase on GBS gene regulation and FRT colonization. IMPORTANCE Group B Streptococcus (GBS) colonizes the female reproductive tract (FRT) in one-third of women, and carriage leads to numerous adverse pregnancy outcomes including the preterm premature rupture of membranes, chorioamnionitis, and stillbirth. The presence of GBS in the FRT during pregnancy is also the largest predisposing factor for the transmission of GBS and invasive neonatal diseases, including pneumonia, sepsis, and meningitis. The factors contributing to GBS colonization are still being elucidated. Here, we show for the first time that GBS transcription is regulated by an orphan DNA cytosine methyltransferase (Dcm). Many GBS factors are regulated by Dcm, especially those involved in carbohydrate transport and metabolism. We show that GBS persistence in the FRT is dependent on the catabolism of sugars found on the vaginal mucin MUC5B. Collectively, this work highlights the regulatory importance of a DNA methyltransferase and identifies both host and bacterial factors required for GBS colonization.

Dataset Information

Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.

Publications

Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.

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