Maternal Infection By Group B Streptococcus Induces Sex-Specific Maternofetal Inflammatory Signaling Leading to Postnatal ASD-like Behaviors in Males

Background: Placental infection and/or inflammation (chorioamnionitis) is a common complication associated with adverse outcomes including premature birth and brain injuries leading to neurodevelopmental disabilities such as autism spectrum disorder (ASD). Chorioamnionitis is a polymicrobial infection most often due to ascending genital pathogens. Group B Streptococcus (GBS) is a gram-positive bacterium colonizing the urogenital tract of 20-30% of pregnant women. GBS is isolated in 15% of chorioamnionitis, i.e. twice as often as the gram-negative bacterium Escherichia coli (Tita & Andrews, Clin Perinatol, 2010). Chorioamnionitis is characterized by the release of neurotoxic inflammatory mediators affecting placental synthesis of neurotrophic factors, and potentially disrupting neuroglial fiber tracts in the developing brain. Dysregulation of specific proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6, in maternofetal tissues have been associated with higher risks of having a child with ASD. We previously developed a rat model of end-gestational GBS infection that induces histological chorioamnionitis, characterized by an increased density of neutrophil cells in placentas associated with male versus female fetuses. Following natural birth, male – but not female – offspring in utero-exposed to GBS presented ASD-like behavioral impairments (Allard et al., Autism Research, 2016). We hypothesized that a differential activation of proinflammatory mediators and cells according to the fetal sex is responsible for sex-specific neurobehavioral outcomes in GBS-exposed offspring.

Objectives: Mapping out the expression profiles of cytokines and innate immune cells within GBS-infected placentas, and comparing this immune profile between male and female tissues.

Methods: Lewis dams were injected intraperitoneally on gestational day 19 with β-hemolytic serotype Ia GBS (10⁸ CFU) or saline (control; CTL). Caesarean-sections were performed at 24 h, 48 h and 72 h post-injection to collect maternofetal tissues (placentas, maternal and fetal blood, fetal brains), and to investigate sex-specific maternofetal immune activation and prenatal brain injuries (GBS: n = 18, CTL: n = 14). Proinflammatory cytokines IL-1β, TNF-α and IL-6 were studied by ELISA and immunohistochemistry.

Results: At 24 h, no difference in titers of IL-1β, TNF-α and IL-6 in maternal sera was detected between experimental conditions. At 48 h, increased titers of IL-1β, but not TNF-α and IL-6, were detected in GBS-exposed maternal sera and GBS-exposed male placentas compared to control tissues. At 72 h, increased titers of IL-1β, TNF-α and IL-6 were detected maternal sera, male placentas, and male fetuses’ sera versus CTL tissues. At 72 h, increased levels of IL-1β, TNF-α and IL-6 were detected in GBS-exposed male versus GBS-exposed female placentas. The correlation between maternofetal inflammatory responses and fetal forebrain injuries will be characterized by ongoing studies.

Conclusions: These results suggest that IL-1β might be implicated in the induction of the male-specific forebrain injuries, and subsequent ASD-like behaviors observed in this rat model. Innovative insights into the mechanistic underpinning the pathophysiology of pathogen-induced placental injuries are needed to develop appropriate novel therapeutic interventions.