Nitric Oxide Production and Effects in Group B Streptococcus Chorioamnionitis

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Abstract

Intrauterine infection, or chorioamnionitis, due to group B Streptococcus (GBS) is a common cause of miscarriage and preterm birth. To cause chorioamnionitis, GBS must bypass maternal-fetal innate immune defenses including nitric oxide (NO), a microbicidal gas produced by nitric oxide synthases (NOS). This study examined placental NO production and its role in host-pathogen interactions in GBS chorioamnionitis. In a murine model of ascending GBS chorioamnionitis, placental NOS isoform expression quantified by RT-qPCR revealed a four-fold expression increase in inducible NOS, no significant change in expression of endothelial NOS, and decreased expression of neuronal NOS. These NOS expression results were recapitulated ex vivo in freshly collected human placental samples that were co-incubated with GBS. Immunohistochemistry of wild type C57BL/6 murine placentas with GBS chorioamnionitis demonstrated diffuse inducible NOS expression with high-expression foci in the junctional zone and areas of abscess. Pregnancy outcomes between wild type and inducible NOS-deficient mice did not differ significantly although wild type dams had a trend toward more frequent preterm delivery. We also identified possible molecular mechanisms that GBS uses to survive in a NO-rich environment. In vitro exposure of GBS to NO resulted in dose-dependent growth inhibition that varied by serovar. RNA-seq on two GBS strains with distinct NO resistance phenotypes revealed that both GBS strains shared several detoxification pathways that were differentially expressed during NO exposure. These results demonstrate that the placental immune response to GBS chorioamnionitis includes induced NO production and indicate that GBS activates conserved stress pathways in response to NO exposure.

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