Abstract

Morbidity and mortality of human newborns are significant public health concerns. Predominant risk factors for neonatal morbidity and mortality are invasive bacterial infections and the ensuing severe inflammatory response, which mainly begin in utero. Group B Streptococci (GBS) are a significant cause of preterm births, stillbirths and early onset neonatal disease. Factors that facilitate ascending GBS infection from the lower genital tract to the fetus are not understood. Our studies indicate that upregulation of virulence factors facilitate GBS invasion of placental membranes in vitro. Using human placental membranes and a nonhuman primate model, the objective of this proposal is to mechanistically define how virulence factors enable ascending in utero GBS infection and subsequent fetal lung and brain injury.

Public Health Relevance

Understanding mechanisms of ascending GBS infection and fetal injury will be beneficial for development of therapeutic strategies against in utero infectios that lead to fetal injury, preterm births, and stillbirths.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI100989-05
Application #
9096008
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
GU, Xin-Xing
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101

  Publications

Walker, Christie L; Merriam, Audrey A; Ohuma, Eric O et al. (2018) Femur-sparing pattern of abnormal fetal growth in pregnant women from New York City after maternal Zika virus infection. Am J Obstet Gynecol 219:187.e1-187.e20
Adams Waldorf, Kristina M; Olson, Erin M; Nelson, Branden R et al. (2018) The Aftermath of Zika: Need for Long-Term Monitoring of Exposed Children. Trends Microbiol 26:729-732
Dudley, Dawn M; Van Rompay, Koen K; Coffey, Lark L et al. (2018) Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med 24:1104-1107
Vornhagen, Jay; Armistead, Blair; Santana-Ufret, Verónica et al. (2018) Group B streptococcus exploits vaginal epithelial exfoliation for ascending infection. J Clin Invest 128:1985-1999
Gendrin, Claire; Shubin, Nicholas J; Boldenow, Erica et al. (2018) Mast cell chymase decreases the severity of group B Streptococcus infections. J Allergy Clin Immunol 142:120-129.e6
Vornhagen, Jay; Quach, Phoenicia; Santana-Ufret, Verónica et al. (2018) Human Cervical Mucus Plugs Exhibit Insufficiencies in Antimicrobial Activity Towards Group B Streptococcus. J Infect Dis 217:1626-1636
Gendrin, Claire; Merillat, Sean; Vornhagen, Jay et al. (2018) Diminished Capsule Exacerbates Virulence, Blood-Brain Barrier Penetration, Intracellular Persistence, and Antibiotic Evasion of Hyperhemolytic Group B Streptococci. J Infect Dis 217:1128-1138
Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374
Mitchell, Timothy; MacDonald, James W; Srinouanpranchanh, Sengkeo et al. (2018) Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in nonhuman primates. Am J Obstet Gynecol 218:438.e1-438.e16
Lannon, Sophia M R; Adams Waldorf, Kristina M; Fiedler, Tina et al. (2018) Parallel detection of lactobacillus and bacterial vaginosis-associated bacterial DNA in the chorioamnion and vagina of pregnant women at term. J Matern Fetal Neonatal Med :1-9

Showing the most recent 10 out of 32 publications