Preterm birth is a leading cause of neonatal morbidity and mortality. Although microbial invasion of the amniotic cavity (MIAC) is associated with most early preterm births, the temporal events that occur during MIAC and preterm labor are not known. Group B streptococci (GBS) are b-hemolytic, Gram-positive bacteria, which commonly colonize the vagina but have been recovered from the amniotic fluid in preterm birth cases. To understand temporal events that occur during MIAC, we used a chronically catheterized nonhuman primate model that closely emulates human pregnancy. This model allows monitoring of uterine contractions, timing of MIAC, and immune responses during pregnancy-associated infections. We show that adverse outcomes such as preterm labor, MIAC, and fetal sepsis were observed more frequently during infection with hemolytic GBS when compared with nonhemolytic GBS. Although MIAC was associated with systematic progression in chorioamnionitis beginning with chorionic vasculitis and progressing to neutrophilic infiltration, the ability of the GBS hemolytic pigment toxin to induce neutrophil cell death and subvert killing by neutrophil extracellular traps (NETs) in placental membranes in vivo facilitated MIAC and fetal injury. Furthermore, compared with maternal neutrophils, fetal neutrophils exhibit decreased neutrophil elastase activity and impaired phagocytic functions to GBS. Collectively, our studies demonstrate how a bacterial hemolytic lipid toxin enables GBS to circumvent neutrophils and NETs in placental membranes to induce fetal injury and preterm labor.
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We are grateful to the participants who participated in our study. We thank A. Gest, J. Hamanishi, G. Heidel, D. Power, J. Karlinsey, and C. Hughes for their assistance. We acknowledge C. Rubens and M. Gravett for study design related to the performance of the original NHP experiments. This work was supported by the NIH (grant R01AI100989 to L.R. and K.M.A.W.; grants R56AI070749, R01AI112619, and R21AI109222 to L.R.; and grant P30HD002274). The NIH training grants T32 HD007233 (principal investigator: L. Frenkel) and T32 AI07509 (principal investigator: L. A. Campbell) supported E.B. and J.V., respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
2016 © The Authors.