Reproductive tract infections (RTI) are of particular relevance during pregnancy and have important implications for maternal and neonatal health. Both bacterial vaginosis and group B Streptococcus are RTI associated with biofilm formation and long-term colonization of the vaginal mucosal surface. We have found that both Gardnerella vaginalis (the major constituent of the vaginal microbiota during bacterial vaginosis) and group B Streptococcus (the leading cause of early-onset sepsis in newborns) form biofilms that contain extracellular DNA and are sensitive to the activity of exogenous DNase. Thus, we hypothesize that an intravaginal DNase gel could decrease the risk of these and potentially other RTI in late pregnancy. Our overall goal is to rigorously evaluate this hypothesis by formulating a lead candidate DNase gel for in vitro and in vivo testing and by leveraging our experience in microbicide acceptability studies to determine potential barriers to the real-world use of such a preventive strategy during pregnancy. In the proposed sequential R21/R33 phased innovation study, the R21 phase will focus on formulation of DNase gel prototypes and evaluation of efficacy against RTI relevant to pregnancy using in vitro and in vivo models and on developing behavioral instruments to study microbicide acceptability in pregnant women. In the R33 phase, we will optimize the lead gel candidate, perform expanded efficacy and toxicology studies in vivo, and use our behavioral instrument to study locally and nationally representative populations of pregnant women. At the conclusion of the two phases, we will have completed a detailed preclinical evaluation of a DNase gel for the prevention of two important RTI in pregnancy and will have performed an assessment of behavioral factors important to the implementation of such a strategy. If a suitable gel advances to the conclusion of the R33 phase with in vivo efficacy and an acceptable toxicologic profile, we will move forward with the eventual goal of human testing.

Public Health Relevance

Reproductive tract infections (RTI) are a major cause of disease in pregnant women and newborns. In this proposal, we will perform preclinical evaluation of a new non-antibiotic strategy for prevention of two of the most common RTI in pregnancy. We will study both the biological and the psychological/behavioral impact of such a strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI098654-01
Application #
8265110
Study Section
Special Emphasis Panel (ZAI1-JKB-M (J3))
Program Officer
Deal, Carolyn D
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$253,209
Indirect Cost
$83,275
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Los, Ferdinand C O; Randis, Tara M; Aroian, Raffi V et al. (2013) Role of pore-forming toxins in bacterial infectious diseases. Microbiol Mol Biol Rev 77:173-207
Kulkarni, Ritwij; Randis, Tara M; Antala, Swati et al. (2013) *-Hemolysin/cytolysin of Group B Streptococcus enhances host inflammation but is dispensable for establishment of urinary tract infection. PLoS One 8:e59091
Randis, Tara M; Zaklama, Joanne; LaRocca, Timothy J et al. (2013) Vaginolysin drives epithelial ultrastructural responses to Gardnerella vaginalis. Infect Immun 81:4544-50
Planet, Paul J; Narechania, Apurva; Hymes, Saul R et al. (2013) Bordetella holmesii: initial genomic analysis of an emerging opportunist. Pathog Dis 67:132-5
Hymes, Saul R; Randis, Tara M; Sun, Thomas Yang et al. (2013) DNase inhibits Gardnerella vaginalis biofilms in vitro and in vivo. J Infect Dis 207:1491-7
Planet, Paul J; Rampersaud, Ryan; Hymes, Saul R et al. (2013) Genome Sequence of the Human Abscess Isolate Streptococcus intermedius BA1. Genome Announc 1: