Group B Streptococcal Infection of the Choriodecidua Induces Dysfunction of the Cytokeratin Network in Amniotic Epithelium: A Pathway to Membrane Weakening

PLoS Pathogens

Lakshmi Rajagopal¹  Craig J. Bierle¹  Min Spencer²  Mei Deng²  Aasthaa Bansal³  Federico M. Farin⁴  Richard P. Beyer⁴  Theo K. Bammler⁴  Jeroen P. Vanderhoeven⁵  Michael G. Gravett⁵  Ryan M. McAdams⁶  Kristina M. Adams Waldorf⁶  Raj P. Kapur⁷  Craig E. Rubens⁸ 

[1] Center for Childhood Infections and Prematurity Research, Seattle Children's Research Institute, Seattle, Washington, United States of America;Center on Human Development and Disability, University of Washington, Seattle, Washington, United States of America;Department of Biostatistics, University of Washington, Seattle, Washington, United States of America;Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America;Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, United States of America;Department of Pediatrics, University of Washington, Seattle, Washington, United States of America;Departments of Pathology, Seattle Children's and University of Washington, Seattle, Washington, United States of America;Global Alliance to Prevent Prematurity & Stillbirth, Seattle, Washington, United States of America

关键词: Gene expression;    Apoptosis;    Macaque;    Intermediate filaments;    Epithelium;    Cytokines;    Chorioamnionitis;    Preterm birth;   

DOI  :  10.1371/journal.ppat.1003920

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received choriodecidual inoculation of either GBS (n = 5) or saline (n = 5). Cesarean section was performed in the first week after GBS or saline inoculation. RNA extracted from chorioamnion (inoculation site) was profiled by microarray. Single gene, Gene Set, and Ingenuity Pathway Analysis results were validated using qRT-PCR (chorioamnion), Luminex (amniotic fluid, AF), immunohistochemistry, and transmission electron microscopy (TEM). Despite uterine quiescence in most cases, significant elevations of AF cytokines (TNF-α, IL-8, IL-1β, IL-6) were detected in GBS versus controls (p<0.05). Choriodecidual infection resolved by the time of cesarean section in 3 of 5 cases and GBS was undetectable by culture and PCR in the AF. A total of 331 genes were differentially expressed (>2-fold change, p<0.05). Remarkably, GBS exposure was associated with significantly downregulated expression of multiple cytokeratin (CK) and other cytoskeletal genes critical for maintenance of tissue tensile strength. Immunofluorescence revealed highly significant changes in the CK network within amniocytes with dense CK aggregates and retraction from the cell periphery (all p = 0.006). In human pregnancies affected by PPROM, there was further evidence of CK network retraction with significantly shorter amniocyte foot processes (p = 0.002). These results suggest early choriodecidual infection results in decreased cellular membrane integrity and tensile strength via dysfunction of CK networks. Downregulation of CK expression and perturbations in the amniotic epithelial cell intermediate filament network occur after GBS choriodecidual infection, which may contribute to PPROM.

【 授权许可】

CC BY