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Title page for ETD etd-12132018-144612


Type of Document Dissertation
Author Doster , Ryan Steven
URN etd-12132018-144612
Title Streptococcus agalactiae infection of gestational tissues induces innate immune responses including the release of placental macrophage extracellular traps
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Timothy L. Cover, M.D. Committee Chair
David M. Aronoff, M.D. Committee Member
Eric P. Skaar, Ph.D. Committee Member
Leslie J. Crofford, M.D. Committee Member
Steven D. Townsend, Ph.D. Committee Member
Keywords
  • Group B Streptococcus
  • macrophage
  • extracellular trap
  • biofilm
  • perinatal infection
Date of Defense 2018-12-03
Availability restrictone
Abstract
Streptococcus agalactiae, also known as Group B Streptococcus (GBS) is a common perinatal pathogen, and GBS vaginal colonization is a major risk factor for infection-related adverse pregnancy outcomes including preterm birth, chorioamnionitis, and neonatal sepsis. Despite the prevalence and impact of perinatal infections, knowledge gaps remain regarding mechanisms by which bacterial infections precipitate outcomes such as preterm birth and neonatal sepsis. This work investigates interactions between gestational tissues and bacterial pathogens that lead to adverse pregnancy outcomes. In an ex vivo model of chorioamnionitis using human fetal membrane tissues, GBS and perinatal pathogens, Escherichia coli and Staphylococcus aureus, form biofilms on the choriodecidual surface of membrane tissues, which were detected by scanning electron microscopy and Raman microspectroscopy. GBS was found to penetrate membrane tissue layers. In response infection, fetal membrane tissues release proinflammatory cytokines associated with intrauterine infection. GBS infection stimulated trafficking of leukocytes into gestational tissues in the ex vivo chorioamnionitis model and in an in vivo mouse model of ascending pregnancy infection. In response to ex vivo GBS infection, neutrophils and placental macrophages release extracellular traps composed of cellular DNA that are studded with proteases and antimicrobial proteins. Placental macrophage extracellular trap (MET) release occurred via a oxidative-burst dependent mechanism, and METs were identified in the ex vivo chorioamnionitis model, suggesting MET release occurs during chorioamnionitis. GBS infection of placental macrophages also resulted in release of matrix metalloproteinases that are associated with fetal membrane degradation. Placental macrophage responses may provide protection against invading bacterial pathogens through trapping and killing bacteria but may also release important mediators of fetal membrane extracellular matrix digestion that could potentially contribute to infection-related pathologies including preterm rupture of membrane and preterm birth. Cumulatively, this work identifies innate immune responses in gestational tissues to bacterial infection that contribute to pathways that culminate in adverse pregnancy outcomes.
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