Feto-placental infections represent a major cause for pregnancy complications, yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Organisms known to cause feto-placental infection are predominantly intracellular pathogens. Among those is Listeria monocytogenes, which is highly amenable to experimental analysis. We propose to use L. monocytogenes as a model intracellular pathogen to understand the mechanisms of transplacental transmission. We have developed a pregnant guinea pig model of listeriosis which mimics human disease. A single layer of trophoblasts separates fetal from maternal circulation in the placenta of humans and guinea pigs. We propose to characterize the interaction between L. monocytogenes and trophoblasts in vivo and to identify listerial virulence factors that are necessary for feto-placental infection. In addition to forming a physical barrier trophoblasts are thought to be part of the innate immune response to infection. We propose to analyze gene expression in trophoblasts in response to infection with L. monocytogenes by microarray analysis. Understanding the mechanisms of transplacental transmission will help in designing more effective means of treatment and disease prevention. The applicant is a board certified pediatrician and is affiliated with the Department of Infectious Diseases at Children's Hospital Oakland, CA. She has initiated this project with support from the Pediatric Scientist Development Program and intends to continue her studies with support from this application. The research will be conducted in the laboratory of Prof. Daniel A. Portnoy at UC Berkeley, who heads a laboratory that has been instrumental in establishing L. monocytogenes as a model for host-pathogen interactions. The proposed research will provide important training which will prove crucial for the applicant when she becomes an independent physician scientist, her long-term goal.
|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|
|Robbins, Jennifer R; Skrzypczynska, Kasia M; Zeldovich, Varvara B et al. (2010) Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes. PLoS Pathog 6:e1000732|
|Bakardjiev, Anna I; Theriot, Julie A; Portnoy, Daniel A (2006) Listeria monocytogenes traffics from maternal organs to the placenta and back. PLoS Pathog 2:e66|