Placental Infection By Group B Streptococcus Induces Sex-Specific Maternofetal Inflammatory Responses Associated with ASD-like Behaviors in Males

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
M. J. Allard1, A. Giraud2, M. Segura3 and G. Sebire1, (1)Pediatrics, McGill University, Montreal, QC, Canada, (2)Pediatrics and Neonatal Intensive Care Unit, Saint-Etienne University Hospital, Saint-Etienne, France, (3)Pathology and Microbiology, Universite de Montreal, St-Hyacinthe, QC, Canada
Background: Clinical and preclinical evidence support relationships between placental infection and inflammation (chorioamnionitis), preterm births and brain damage, contributing to disorders including autism spectrum disorder (ASD). Group B Streptococcus (GBS) is isolated in 15% of chorioamnionitis. Changes in placental histology may impact fetal outcomes by altering nutrient transport, hormone production, as well as inflammatory factor releases in fetal circulation. Dysregulation of proinflammatory cytokines in maternofetal tissues has been associated with higher risks of having a child with ASD. Placental infection by GBS in rats has been shown to induce a histological chorioamnionitis - characterized by an increased density of polymorphonuclear cells (PMN) in male compared to female placentas - and led to ASD-like behavioral impairments in males (Allard et al., Autism Research, 2017). In human, males are known to be more sensitive to maternal infection, which convey increased risks for long-term cognitive and behavioral deficits. We hypothesized that placental infection by GBS will induce sex-specific inflammatory processes associated with increased PMN infiltrates in male versus female placentas.

Objectives: To map out the PMN recruitment and expression profiles of PMN-associated cytokines and chemokines within GBS-infected placentas, and comparing this immune profile between male and female tissues.

Methods: Lewis rats were injected intraperitoneally on gestational day 19 with β-hemolytic serotype Ia GBS (108 CFU) or saline (controls). Caesarean-sections were performed at 24, 48 and 72 h post-injection to collect maternofetal tissues (placenta, maternal and fetal blood). Placental GBS and PMN infiltrates, the PMN chemoattractant CINC-1/CXCL1, the alarmin S100A9, and proinflammatory (interleukin(IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-18) and anti-inflammatory (IL-10) cytokines' expressions were measured by ELISA and immunohistochemistry.

Results: At 72 h post-inoculation, GBS-exposed male placentas presented increased PMN densities compared to same-sex controls and a 3.0-fold increase compared to litter-matched GBS -exposed females. GBS-infected placentas associated with males – but not females – presented increased CINC-1 titers at 72 h. Both male and female placentas exposed to GBS displayed increased titers of S100A9, although levels were higher in males compared to females at 72 h. GBS-infected placentas displayed increased titers of IL-1β, TNF-α, IL-6 and IL-10 in both sexes at 48 and 72 h, and sole IL-1β titers were higher in males compared to females at 72 h. The detected levels of IL-1β were correlating positively with levels of CINC-1 in GBS-exposed male placentas. At 72 h, an increased concentration of IL-1β was detected in the sera of GBS-exposed male – but not female – fetuses. At 48 and 72 h, increased titers of IL-1β, TNF-α, IL-6, and CINC-1 were detected in GBS-exposed maternal sera.

Conclusions: Our results suggest the implication of IL-1β - triggering the production of CINC-1 - in the induction of sex-specific PMN infiltrates. The sex-specific placental and fetal inflammatory responses we uncovered are interesting in regard to the higher susceptibility of the male population for preterm birth, brain injuries and ASD. Innovative insights into the mechanistic underpinning the pathophysiology of pathogen-induced placental injuries are needed to identify prenatal maternal biomarkers, and to develop appropriate novel therapeutic interventions.

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See more of: Animal Models