c-section-preclinical-animal-model-chorioamnionitis-triggered-group-b

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B <em>Streptococcus</em> (GBS)

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, ...

McGill University

Group B Streptococcus (GBS) is a commensal bacterium present in the lower genital tract of 15-30% of healthy pregnant women. GBS is the leading cause of chorioamnionitis and cerebral injuries in newborns, occurring most often in the absence of maternofetal pathogen translocation. Despite GBS being the most frequent bacterium colonizing pregnant women, no preclinical studies have investigated the impact of end-gestational maternal GBS exposure on the offspring's brain development and its behavioral correlates. Our hypothesis is that GBS-induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring. Our goal was to study the impact of maternal GBS infection on the placental and neurodevelopmental features in the offspring using a new preclinical rat model. GBS-exposed placentas exhibited chorioamnionitis characterized by the presence of Gram-positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring. GBS-exposed male offspring had reduced thickness of periventricular white matter. In addition, they exhibited autistic-like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity. Overall, these data show for the first time that gestational exposure to GBS plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD). These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology. Autism Res 2017, 10: 233-245. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation.

Infection or inflammation during pregnancy is known to lead to maternal immune activation triggering a fetal inflammatory response syndrome associated with deleterious effects, such as brain injury and neurodevelopmental disabilities. Group B Streptococcus (GBS) - one of the most common bacterium colonizing pregnant women - can be responsible for chorioamnionitis. Given that interleukin (IL)-1β has a major role in anti-GBS host defense, we hypothesized that IL-1β-driven innate immune response is implicated in GBS-induced chorioamnionitis. Using a rat model of GBS-induced chorioamnionitis, this study showed that inflammatory response to this pathogen was associated with maternal and placental IL-1β hyper expression. Following placental chemokine (C-X-C motif) ligand 1 (CXCL1) production, polymorphonuclear leukocytes (PMN) placental infiltration started at 24 h post-GBS exposure, and MMP-10 was released within these placentas. At 72 h, PMN infiltration extended to membranes and to membranes' arteries. This was associated with IL-1β release within the fetus blood at 72 h. Such a GBS-associated inflammatory cascade might be deleterious for fetal organs. These results pave the way toward targeted placento-protective anti-inflammatory strategies against GBS-induced chorioamnionitis.

Activation of the IL-1β/CXCL1/MMP-10 axis in chorioamnionitis induced by inactivated Group B Streptococcus.

Group B Streptococcus (GBS) is one the most common bacterium responsible of maternal infections during pregnancy. Offspring in utero-exposed to GBS-induced placental inflammation displayed sex-specific forebrain injuries. Sex differences have been reported in several neuropsychiatric disorders. Hence, we hypothesized that female rats in utero-exposed to GBS may present sex-specific neurobehavioral impairments. Lewis rats were injected intraperitoneally every 12 h from gestational day (G) 19 to G22 with either saline (controls) or inactivated serotype Ia GBS (10 CFU). Before puberty, no difference in terms of spontaneous motor activity, exploratory or anxiety-related behaviors was noticed between experimental conditions. During puberty, GBS-exposed females - but not males - performed worse than same-sex controls in a forced motor task. During adulthood, GBS-exposed females - but not males - displayed increased spontaneous locomotor activity and decreased inhibition. In conclusion, our findings show for the first time that adult females - but not males - in utero-exposed to GBS-induced inflammation presented a hyperactive and disinhibited phenotype emerging after puberty.

Hyperactive behavior in female rats in utero-exposed to group B Streptococcus-induced inflammation.

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.

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

Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death.

Ampicillin Treatment Increases Placental Interleukin-1 Beta Concentration and Polymorphonuclear Infiltration in Group B Streptococcus-Induced Chorioamnionitis: A Preclinical Study.

To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA).

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

Group B  (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 10 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1β and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.

Marie-Julie Allard

Department of Pediatrics

McGill University

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS)