Infection and inflammation at the maternal-fetal interface lead to preterm labor, a major source of human morbidity and mortality. The underlying mechanisms of preterm labor remain elusive. Therefore, no effective therapies exist to-date. The maternal-fetal interface is unique because fetal cells are juxtaposed to maternal immune cells. How maternal-fetal tolerance is achieved is still poorly understood. Even less is known about host-pathogen interactions in this tissue. Evidence is accumulating that the maternal-fetal interface has strong and unique innate host defenses, suggesting that specific virulence determinants might be necessary to achieve microbial colonization. The overall goal of this research application is to understand host-pathogen interactions at the maternal-fetal interface, and to identify innate host defense pathways that protect the fetus from infection. Among the pathogens that are able to infect the maternal-fetal interface is Listeria monocytogenes, a facultative intracellular bacterium; and our model organism because it is extremely amenable to experimental analysis. We developed a pregnant guinea pig model of listeriosis that replicates human disease for in vivo studies. In addition, we have developed highly relevant model systems of human placentation, to perform in vitro experiments in systems that are physiologically highly relevant. Using these models we have identified a secreted bacterial protein specifically important for infection of the maternal-fetal interface. Further, we have discovered that a unique fetal cell population in the uterus (invasive trophoblasts) is able to restrict intracellular bacterial growth.
In Aims 1 and 2 we will determine the functional roles of the placenta-specific virulence determinant that we have discovered.
In Aim 3, we will identify pathways that are important for host defenses in invasive trophoblasts and test whether the placenta-specific virulence determinant we have identified interferes with these pathways. These studies will expand our knowledge of the pathogenesis of placental infections and will serve as a springboard for the development of novel strategies for prevention and therapy of preterm labor.

Public Health Relevance

Intrauterine infection leading to preterm labor is a major cause for morbidity and mortality in newborns and surviving children. The placenta and pregnant uterus form a unique tissue because the fetus has to be protected from rejection by the maternal immune system and from pathogens. Our studies will identify host- pathogen interactions at the maternal-fetal interface, and identify pathways that trigger preterm labor. These studies are a necessary prerequisite for development of novel strategies to prevent and treat preterm labor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084928-07
Application #
9059441
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mills, Melody
Project Start
2010-07-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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Morrison, Holly A; Lowe, David; Robbins, Jennifer R et al. (2018) In Vivo Virulence Characterization of Pregnancy-Associated Listeria monocytogenes Infections. Infect Immun 86:
Rizzuto, Gabrielle; Tagliani, Elisa; Manandhar, Priyanka et al. (2017) Limited Colonization Undermined by Inadequate Early Immune Responses Defines the Dynamics of Decidual Listeriosis. Infect Immun 85:
Rizzuto, Gabrielle A; Kapidzic, Mirhan; Gormley, Matthew et al. (2016) Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface. J Vis Exp :
Faralla, Cristina; Rizzuto, Gabrielle A; Lowe, David E et al. (2016) InlP, a New Virulence Factor with Strong Placental Tropism. Infect Immun 84:3584-3596
Vigliani, Marguerite B; Bakardjiev, Anna I (2014) Intracellular Organisms as Placental Invaders. Fetal Matern Med Rev 25:332-338
Zeldovich, Varvara B; Clausen, Casper H; Bradford, Emily et al. (2013) Placental syncytium forms a biophysical barrier against pathogen invasion. PLoS Pathog 9:e1003821
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Robbins, Jennifer R; Bakardjiev, Anna I (2012) Pathogens and the placental fortress. Curr Opin Microbiol 15:36-43
Melton-Witt, Jody A; Rafelski, Susanne M; Portnoy, Daniel A et al. (2012) Oral infection with signature-tagged Listeria monocytogenes reveals organ-specific growth and dissemination routes in guinea pigs. Infect Immun 80:720-32

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