Risk Factors for Infant Colonization by Hypervirulent CC17 Group B Streptococcus: Toward the Understanding of Late-onset Disease

Tazi, Asmaa; Plainvert, Céline; Anselem, O.; Ballon, Morgane; Marcou, Valérie; Seco, Aurélien; Alaoui, Fatma El; Joubrel, Caroline; Helali, Najoua El; Falloukh, Emile; Frigo, Amandine; Raymond, Josette; Trieu-Cuot, Patrick; Branger, Catherine; Monnier, Alban Le; Azria, Élie; Ancel, Pierre–Yves; Jarreau, Pierre Henri; Mandelbrot, Laurent; Goffinet, François; Poyart, Claire

doi:10.1093/cid/ciz033

Cited by 54 publications

(62 citation statements)

References 21 publications

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“…Besides, HvgA confers gut colonization capacities in murine models and it was presumed that CC17 GBS association with LOD was related to an increased ability of CC17 GBS to colonize neonates compared to other GBS clones (Tazi et al, 2010). However, a recent large prospective cohort study of infant colonization by GBS showed that instead of colonizing neonates more efficiently than other GBS clones, CC17 GBS was associated with a higher risk of delayed post-delivery colonization (Tazi et al, 2019). Together with our findings, these results suggest that the important responsibility of CC17 GBS in LOD relies i) on its improved capacity to establish in the infant developing and versatile microbiota, advantage which is likely conferred by HvgA, and ii) on Srr2-mediated ability to use M cells to cross the intestinal barrier and eventually to disseminate.…”

Section: Discussionmentioning

confidence: 99%

Perinatal hormones favor CC17 group B Streptococcus intestinal translocation through M cells and hypervirulence in neonates

Hays

Touak

Bouaboud

et al. 2019

eLife

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Group B Streptococcus (GBS) is the leading cause of invasive bacterial neonatal infections. Late-onset diseases (LOD) occur between 7 and 89 days of life and are largely due to the CC17 GBS hypervirulent clone. We studied the impact of estradiol (E2) and progesterone (P4), which impregnate the fetus during pregnancy, on GBS neonatal infection in cellular and mouse models of hormonal exposure corresponding to concentrations found at birth (E2-P4 C0) and over 7 days old (E2-P4 C7). Using representative GBS isolates, we show that E2-P4 C7 concentrations specifically favor CC17 GBS meningitis following mice oral infection. CC17 GBS crosses the intestinal barrier through M cells. This process mediated by the CC17-specific surface protein Srr2 is enhanced by E2-P4 C7 concentrations which promote M cell differentiation and CC17 GBS invasiveness. Our findings provide an explanation for CC17 GBS responsibility in LOD in link with neonatal gastrointestinal tract maturation and hormonal imprint.

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Section: Discussionmentioning

confidence: 99%

Perinatal hormones favor CC17 group B Streptococcus intestinal translocation through M cells and hypervirulence in neonates

Hays

Touak

Bouaboud

et al. 2019

eLife

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“…3e5 Vaginal colonization with GBS occurs in approximately 18% of pregnant women worldwide 6 and has been linked with preterm birth (PTB), 2,7e9 preterm premature rupture of membranes (PROM), 10 and neonatal intensive care unit (NICU) admission. 11 GBS vaginal colonization is a risk factor for neonatal transmission during delivery 12,13 and to infants during the postnatal period 14 and is associated with a 3-fold increased rate of NICU admission. 11 GBS in the vagina during pregnancy can also invade through the cervix to cause uteroplacental and fetal infections.…”

Section: Introductionmentioning

confidence: 99%

Gardnerella vaginalis promotes group B Streptococcus vaginal colonization, enabling ascending uteroplacental infection in pregnant mice

Gilbert

Foster

Cao³

et al. 2021

American Journal of Obstetrics and Gynecology

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BACKGROUND: Group B Streptococcus is a common vaginal bacterium and the leading cause of invasive fetoplacental infections. Group B Streptococcus in the vagina can invade through the cervix to cause ascending uteroplacental infections or can be transmitted to the neonate during vaginal delivery. Some studies have found that women with a "dysbiotic" polymicrobial or Lactobacillus-depleted vaginal microbiota are more likely to harbor group B Streptococcus. Gardnerella vaginalis is often the most abundant bacteria in the vaginas of women with dysbiosis, while being detected at lower levels in most other women, and has been linked with several adverse pregnancy outcomes. Mouse models of group B Streptococcus and Gardnerella vaginalis colonization have been reported but, to the best of our knowledge, the two have not been studied together. The overarching idea driving this study is that certain members of the dysbiotic vaginal microbiota, such as Gardnerella vaginalis, may directly contribute to the increased rate of group B Streptococcus vaginal colonization observed in women with vaginal dysbiosis. OBJECTIVE: We used a mouse model to test the hypothesis that vaginal exposure to Gardnerella vaginalis may facilitate colonization and/or invasive infection of the upper reproductive tract by group B Streptococcus during pregnancy. STUDY DESIGN: Timed-pregnant mice were generated using an allogeneic mating strategy with BALB/c males and C57Bl/6 females. Dams were vaginally inoculated at gestational day 14 with group B Streptococcus alone (using a 10-fold lower dose than previously reported models) or coinoculated with group B Streptococcus and Gardnerella vaginalis. Bacterial titers were enumerated in vaginal, uterine horn, and placental tissues at gestational day 17. The presence (Fisher exact tests) and levels (Mann-Whitney U tests) of bacterial titers were compared between monoand coinoculated dams in each compartment. Relative risks were calculated for outcomes that occurred in both groups. Tissue samples were also examined for evidence of pathophysiology. RESULTS: Inoculation of pregnant mice with 10 7 group B Streptococcus alone did not result in vaginal colonization or ascending infection. In contrast, coinoculation of group B Streptococcus with Gardnerella vaginalis in pregnant mice resulted in a 10-fold higher risk of group B Streptococcus vaginal colonization (relative risk, 10.31; 95% confidence interval, 2.710e59.04; P¼.0006 [Fisher exact test]). Ascending group B Streptococcus infection of the uterus and placenta occurred in approximately 40% of coinoculated animals, whereas none of those receiving group B Streptococcus alone developed uterine or placental infections. Immunofluorescence microscopy revealed group B Streptococcus in both the maternal and fetal sides of the placenta. Histologic inflammation and increased proinflammatory cytokines were evident in the setting of group B Streptococcus placental infection. Interestingly, placentas from dams exposed to group B Streptococcus and Gardnerella vaginalis,...

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“…We hypothesized that srr2 transcription requires an activator such as the Rga-associated regulator present in the distantly related srr1 operon of non-CC17 strains (8, 48), which might be necessary to outcompete the binding of the non-phosphorylated CovR form on the promoter. The integration of multiple regulatory proteins might be necessary to express Srr2 preferentially in the neonatal gut rather than during the invasive phase (7, 49), in contrast to HvgA which has a major role at the onset of meningitis (6).…”

Section: Discussionmentioning

confidence: 99%

“…This correlates with the lower haemolytic activity and the higher level of CovR phosphorylation in BM110 compared to NEM316. The paradox of a more efficient repression of virulence genes in the hypervirulent clone might in fact reflect the clinical characteristic of CC-17 strains which are associated with a delayed colonization of the neonatal gut rather than an increase pathogenicity caused by toxin expression (7, 49, 66).…”

Section: Discussionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

Mazzuoli

Daunesse

Varet

et al. 2021

Preprint

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Virulence of the neonatal pathogen Group B Streptococcus depends on the master regulator CovR. Inactivation of CovR leads to large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, comparative analyses suggested a plasticity of the CovR signalling pathway in clinical isolates, probably due to the host selective pressure and leading to phenotypic heterogeneity in the bacterial population. Here, we characterize the CovR regulatory network in a strain representative of the hypervirulent lineage responsible of the majority of late-onset meningitidis. Genome-wide binding and transcriptome analysis demonstrated that CovR acts as a direct and global repressor of virulence genes, either as a primary regulator or with specialized co-regulators. Remarkably, CovR directly regulates genes of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, as well as core-genes showing mutational biases in the population. Parallel analysis of the CovR network in a second isolate links strain-specificities to micro-evolutions in CovR-regulated promoters and to broad difference due to variability in CovR activation by phosphorylation. Our results highlight the direct, coordinated, and strain-specific regulation of virulence genes by CovR. This intra-species evolution of the signalling network reshapes bacterial-host interactions, increasing the potential for adaptation and the emergence of clone associated with specific diseases.

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Risk Factors for Infant Colonization by Hypervirulent CC17 Group B Streptococcus: Toward the Understanding of Late-onset Disease

Abstract: The hypervirulent group B Streptococcus clone CC17 accounts for the majority of infant late-onset disease (LOD). We provide evidence that the high incidence of CC17 in LOD is likely due to an enhanced post-delivery mother-to-infant transmission.

Cited by 54 publications

References 21 publications

Perinatal hormones favor CC17 group B Streptococcus intestinal translocation through M cells and hypervirulence in neonates

Perinatal hormones favor CC17 group B Streptococcus intestinal translocation through M cells and hypervirulence in neonates

Gardnerella vaginalis promotes group B Streptococcus vaginal colonization, enabling ascending uteroplacental infection in pregnant mice

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

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