Sex-specific maternofetal innate immune responses triggered by group B Streptococci

Marie-Julie Allard,Guillaume Sebire,Antoine Giraud,Mariela Segura

doi:10.1038/s41598-019-45029-x

Abstract

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis, which is a major risk factor for premature birth and brain injuries. Males are at greater risk than females for developing lifelong neurobehavioural disorders, although the origins of this sex bias remain poorly understood. We previously showed that end-gestational inflammation triggered by GBS led to early neurodevelopmental impairments mainly in the male rat progeny. Identifying key inflammatory players involved in maternofetal immune activation by specific pathogens is critical to develop appropriate novel therapeutic interventions. We aimed to map out the GBS-induced profile of innate immune biomarkers in the maternal-placental-fetal axis, and to compare this immune profile between male and female tissues. We describe here that the GBS-induced immune signalling involved significantly higher levels of interleukin (IL)-1β, cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) and polymorphonuclear cells (PMNs) infiltration in male compared to female maternofetal tissues. Although male – but not female – fetuses presented increased levels of IL-1β, fetuses from both sexes in-utero exposed to GBS had increased levels of TNF-α in their circulation. Levels of IL-1β detected in fetal sera correlated positively with the levels found in maternal circulation. Here, we report for the first time that the maternofetal innate immune signalling induced by GBS presents a sexually dichotomous profile, with more prominent inflammation in males than females. These sex-specific placental and fetal pro-inflammatory responses are in keeping with the higher susceptibility of the male population for preterm birth, brain injuries and neurodevelopmental disorders such as cerebral palsy and autism spectrum disorders.

Highlights

One of the most common bacteria causing chorioamnionitis is group B Streptococcus (GBS; Streptococcus agalactiae), which is isolated in about 15% of cases[1,2,3,4]
We provide novel findings that can be summarized as follows: (i) The polymorphonuclear cells (PMNs) density was markedly increased in the labyrinth layer of male compared to female placentas infected by Group B Streptococcus (GBS) serotype Ia; (ii) IL-1β, Cytokine-Induced Neutrophil Chemoattractant-1 (CINC-1)/CXCL1 and S100A9 responses were more prominent in male versus female placentas infected by GBS; and (iii) in contrast to IL-1β, no sex difference was detected for IL-6, Tumor Necrosis Factor-α (TNF-α), and matrix metalloproteinases (MMPs)-8 their levels were increased in GBS-infected placentas
IL-1β is a key player in the placental immune response against GBS infection and PMN infiltration, according to preclinical studies of systemic infection conducted in adults[12,39]

Summary

Introduction

One of the most common bacteria causing chorioamnionitis is group B Streptococcus (GBS; Streptococcus agalactiae), which is isolated in about 15% of cases[1,2,3,4]. In the context of chorioamnionitis, these cytokines induce the release of chemokines (C-X-C), which attract and activate predominantly PMNs that produce prostaglandin and matrix metalloproteinases (MMPs)[14,15]. Www.nature.com/scientificreports such as cerebral palsy, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD)[23,24,25,26] All these perinatal neurobehavioural morbidities affect collectively 1 out of 6 children[27]. The GBS-exposed offspring presented dysmyelinated forebrain white matter reminiscent of those observed in human perinatal injuries[32,33,34] In this same model, end-gestational GBS-induced acute chorioamnionitis was characterised by a more prominent PMN infiltration in placentas of males compared to female offspring, raising the hypothesis of a relationship between the sex-biased inflammatory response and the distinct neurobehavioural phenotypes[32]. We used our model to determine whether GBS-induced chorioamnionitis induces a sexually dichotomous innate inflammatory process driven by IL-1β, IL-1-induced chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) attracting PMNs, and PMN-produced S100A9 and MMP-8

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