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A bacterial hemolytic lipid toxin subverts neutrophils and neutrophil extracellular traps to promote gbs invasion, fetal injury and preterm labor in nonhuman primates

ABSTRACT: Preterm birth is a leading cause of neonatal morbidity and mortality. Microbial infection and inflammation of the amniotic cavity are associated with the majority of early preterm births and thought to arise from ascension of bacteria from the lower genital tract. Group B Streptococci (GBS) are beta-hemolytic, gram-positive bacteria, which commonly colonize the vagina and have been recovered from the amniotic fluid in cases of preterm birth. Host immune defenses that are critical for prevention of microbial invasion of the amniotic cavity (MIAC) and preterm labor are not completely understood. We recently showed that increased expression of the hemolytic pigment promotes GBS penetration of human placenta ex vivo and hyperhemolytic/hyperpigmented GBS strains with mutations in the hemolysin repressor (CovR/CovS) can be isolated from women in preterm labor. To understand placental/ choriodecidual immune responses that are necessary to prevent MIAC and preterm labor, we utilized a unique chronically catheterized nonhuman primate model that closely emulates human pregnancy. We observed that preterm labor, MIAC, and fetal injury occurred significantly more frequently in pregnant nonhuman primates infected with hyperpigmented GBS (ΔcovR) despite the strong induction of proinflammatory responses in the chorioamnion. Placental histopathology revealed a systematic progression in development of chorioamnionitis in GBSΔcovR animals beginning with chorionic vasculitis and subsequently progressing to neutrophilic infiltration in the chorioamnion.

ORGANISM(S): Macaca nemestrina Macaca fascicularis

PROVIDER: GSE80248 | GEO | 2016/04/26

SECONDARY ACCESSION(S): PRJNA318477

REPOSITORIES: GEO

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Project description:Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, precise phenotyping of the preterm birth is hampered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. The studyâ??s aim was to comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor using precisely phenotyped samples. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified the four groups of patients: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). The largest differences in gene expression among the four groups occurred in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5â?? and 3â??UTR regions. The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection. 183 total RNA samples from 8 tissue types collected from 35 women grouped into six categories of pregnancy outcome. One microarray replicate per sample. Other Contributors: Radek Bukowski, Sam Parry and the NICHD Genomic and Proteomic Network for Preterm Birth Research

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A bacterial hemolytic lipid toxin subverts neutrophils and neutrophil extracellular traps to promote gbs invasion, fetal injury and preterm labor in nonhuman primates

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