Placental Group B Streptococcus Infection: Sex Specific Inflammatory Response and Autistic-like Traits in Male Offspring

Background: Group B Streptococcus (GBS) infection is one of the major causes of chorioamnionitis, which is a risk factor for preterm birth and autism spectrum disorder (ASD). Chorioamnionitis affects the placental synthesis of neurotrophic factors, and triggers the release of neurotoxic inflammatory mediators, such as interleukin-1 (IL-1), which might disrupt myelinated neuroglial fiber tracts. We previously showed, using a new rat model, that GBS-induced maternal infection leads to sex-specific forebrain injuries and ASD-like traits in the offspring. Male offspring from GBS-exposed dams presented developmental impairments characterized by ASD-like behaviors with defective: communication, social interactions, and sensory integration. GBS-exposed dams displayed chorioamnionitis characterized by a higher infiltration of polymorphonuclear cells in male than female (Allard et al., Autism Research, 2016). Our hypothesis is that maternal exposure to GBS impacts the placenta through an IL-1 driven inflammatory response leading to brain injuries and ASD-like traits in the offspring.

Objectives: To characterize GBS-induced inflammation on the placenta, and its specific effects on the offspring’ developing brain.

Methods:  Lewis dams were inoculated intraperitoneally on gestational day 19 with live serotype Ia GBS (10⁸ CFU). Caesarian-sections were performed at multiple time points following the infection to collect placentas, and maternal and fetal blood samples. The maternofetal inflammatory response was studied by ELISA and immunohistochemistry. Behavioral tests were performed from postnatal day (P)7 to P40 to assess ASD-like behaviors. Brains were collected at P40 for histological studies. Magnetic resonance imaging and diffusion weighted imaging were performed on young adult rats.

Results: GBS placentas were infected, but did not result in pups’ infection. Following GBS infection, increased titers of IL-1β were detected in maternal blood, male placentas, and male fetuses’ blood, vs control tissues. At P40, GBS-exposed males showed a reduced thickness of the external capsule, of the frontal neocortex and of the corpus callosum, with a decreased mean fractional anisotropy in the anterior part of the corpus callosum. Increased hippocampus areas and increased thickness of the cingulum were also measured in GBS-exposed males at P40, compared to male controls. None of these differences were observed in GBS-exposed females. Placental inflammation and forebrain injuries will be further characterized by ongoing studies.

Conclusions:  Exposure to live GBS induces maternofetal immune activation resulting in neurodevelopmental abnormalities recapitulating those of human ASD, including sex dichotomy and behavioral phenotype. Our findings pave the way towards the use of IL-1 blockade in therapeutic trials aimed to prevent ASD arising from GBS infection, a common and modifiable gestational environmental factor.