Ureaplasma parvum induces preterm birth by triggering immune responses in the fetus and at the maternal-fetal interface

Abstract

Abstract Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every four preterm births is due to intra-amniotic infection, most commonly associated with Ureaplasma species. However, a causal link between Ureaplasma species and adverse pregnancy outcomes, as well as the triggered host immune responses, has not been investigated. Molecular microbiological surveys first revealed that Ureaplasma parvum is the most common bacterium in women with intra-amniotic infection. Ultrasound-guided intra-amniotic injection of U. parvum in pregnant mice resulted in preterm birth and neonatal death. Specific qPCR revealed that U. parvum invaded specific fetal (lung, intestine, spleen, fetal membranes, and placenta) and maternal (decidua, uterus, and cervix) compartments. Consistently, U. parvum induced a strong inflammatory response in the amniotic cavity, fetal membranes, placenta, and fetal lung and spleen, as well as at the maternal-fetal interface. However, U. parvum neither invaded the non-reproductive maternal organs nor induced a maternal systemic inflammatory response. An ex vivo model of intra-amniotic infection showed that U. parvum elicits pro-inflammatory responses in human amnion epithelial cells. Lastly, the treatment of U. parvum-injected mice with clarithromycin, a clinically relevant macrolide, prevented preterm birth and neonatal death. Collectively, this investigation provides a causal link between U. parvum and adverse pregnancy outcomes, and yields insights into the host immune responses triggered by this genital mycoplasma. Importantly, these data support the use of clarithromycin in the treatment of Ureaplasma-associated intra-amniotic infection leading to preterm birth.