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Group B streptococcus exploits vaginal epithelial exfoliation for ascending infection
Jay Vornhagen, … , Elizabeth Nance, Lakshmi Rajagopal
Jay Vornhagen, … , Elizabeth Nance, Lakshmi Rajagopal
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):1985-1999. https://doi.org/10.1172/JCI97043.
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Research Article Infectious disease Reproductive biology Article has an altmetric score of 37

Group B streptococcus exploits vaginal epithelial exfoliation for ascending infection

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Abstract

Thirteen percent of pregnancies result in preterm birth or stillbirth, accounting for fifteen million preterm births and three and a half million deaths annually. A significant cause of these adverse pregnancy outcomes is in utero infection by vaginal microorganisms. To establish an in utero infection, vaginal microbes enter the uterus by ascending infection; however, the mechanisms by which this occurs are unknown. Using both in vitro and murine models of vaginal colonization and ascending infection, we demonstrate how a vaginal microbe, group B streptococcus (GBS), which is frequently associated with adverse pregnancy outcomes, uses vaginal exfoliation for ascending infection. GBS induces vaginal epithelial exfoliation by activation of integrin and β-catenin signaling. However, exfoliation did not diminish GBS vaginal colonization as reported for other vaginal microbes. Rather, vaginal exfoliation increased bacterial dissemination and ascending GBS infection, and abrogation of exfoliation reduced ascending infection and improved pregnancy outcomes. Thus, for some vaginal bacteria, exfoliation promotes ascending infection rather than preventing colonization. Our study provides insight into mechanisms of ascending infection by vaginal microbes.

Authors

Jay Vornhagen, Blair Armistead, Verónica Santana-Ufret, Claire Gendrin, Sean Merillat, Michelle Coleman, Phoenicia Quach, Erica Boldenow, Varchita Alishetti, Christina Leonhard-Melief, Lisa Y. Ngo, Christopher Whidbey, Kelly S. Doran, Chad Curtis, Kristina M. Adams Waldorf, Elizabeth Nance, Lakshmi Rajagopal

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Figure 7

Model of GBS-induced epithelial exfoliation and ascending infection.

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Model of GBS-induced epithelial exfoliation and ascending infection.
Upo...
Upon GBS colonization, integrins are either directly or indirectly activated by GBS. Integrin activation induces phosphorylation of FAK, which in turn phosphorylates AKT, which phosphorylates GSK3β. As adherens junctions break down, β-catenin is released into the cytoplasm. In its dephosphorylated form, GSK3β marks β-catenin for degradation, thus preventing β-catenin stabilization, nuclear translocation, and signaling; however, when it is phosphorylated, it cannot mark β-catenin for degradation, leading to β-catenin stabilization and nuclear translocation. Once in the nucleus, β-catenin stimulates the expression of a variety of genes, including those that drive EMT and epithelial exfoliation. Rather than eliminating colonized GBS, epithelial exfoliation permits bacterial dissemination through the loss of barrier function. This leads to increased ascending infection, which increases the rates of adverse pregnancy outcomes and preterm birth.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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