Infections are a leading cause of pregnancy complications;yet, little is known about their underlying molecular and cellular mechanisms. Our long-term goal is to understand how pathogens breach the immune defenses at the human maternal-fetal interface, causing maternal and fetal morbidity and mortality. We have focused on the human intracellular pathogen Listeria monocytogenes (NIAID Category B Priority Pathogen), which causes pregnancy complications including spontaneous abortion, preterm labor, and neonatal disease. We have developed a novel pregnant guinea pig model of listeriosis that replicates human disease, as the placental architecture of guinea pigs closely resembles humans. We have examined the kinetics of placental infection in this model and found that the placenta is relatively protected from colonization. Our preliminary studies in primary human placental organ cultures corroborate these findings: we have evidence that L. monocytogenes is subjected to multiple bottlenecks when infecting the placenta. We found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection. The main portal of entry into the placenta was a small subpopulation of fetally derived cells (extravillous cytotrophoblasts), which anchor the placenta in the decidua, the lining of the pregnant uterus. Extravillous cytotrophoblasts are not readily accessible from the maternal blood stream, which provides a novel explanation why almost all placental pathogens have intracellular life cycles: they have to reach the decidua inside of maternal cells to spread to the placenta. We also have evidence that cytotrophoblasts are able to inhibit listerial growth and therefore most likely represent the next bottleneck L. monocytogenes has to overcome. We hypothesize that the placenta has evolved multiple mechanisms to resist infection. We propose to use primary human placental cell and organ cultures to characterize how L. monocytogenes breaches the maternal-fetal barrier and how cytotrophoblasts restrict listerial growth. We will test the importance of our findings in vivo in the pregnant guinea pig model of listeriosis.
The specific aims are: (1) To determine the mechanisms utilized by L. monocytogenes to breach the maternal-fetal barrier. (2) To characterize infection of isolated primary placental cells with L. monocytogenes. (3) To characterize the transcriptional response of extravillous cytotrophoblasts to infection with L. monocytogenes.

Public Health Relevance

Infection is a major cause for pregnancy complications, and resultant maternal and fetal morbidity and mortality. The proposed studies will lead to better understanding of the underlying mechanisms, a prerequisite for developing new strategies for prevention and treatment to improve of the health of women and children.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-B (02))
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Mills, Melody
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University of California San Francisco
Schools of Medicine
San Francisco
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Faralla, Cristina; Bastounis, Effie E; Ortega, Fabian E et al. (2018) Listeria monocytogenes InlP interacts with afadin and facilitates basement membrane crossing. PLoS Pathog 14:e1007094
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
Vigliani, Marguerite B; Bakardjiev, Anna I (2013) First trimester typhoid Fever with vertical transmission of salmonella typhi, an intracellular organism. Case Rep Med 2013:973297
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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