Infection and inflammation is a major source for preterm labor, which is the leading cause of mortality in children under 5 years old. Placental infections from pathogens are known to cause several birth complications, including spontaneous abortion, preterm labor, and neonatal sepsis. The placenta is generally resistant to most pathogens, but is particularly susceptible to a subset of intracellular pathogens. This suggests these pathogens exploit a common weakness. However, a molecular and cellular understanding of placental host defenses is lacking. Therefore, our long term goal is to understand the host-pathogen interactions of the placenta that lead to protection or disease. To discover the molecular underpinnings of placental host defenses, we will use the intracellular pathogen Listeria monocytogenes in primary human placental tissues. Similar to all intracellular placental pathogens, L. monocytogenes infects the placenta via a hematogenous route and leads to pregnancy complications. Importantly, L. monocytogenes is a well understood pathogen that has been used to identify several innate immune pathways in multiple cell types. We previously identified that L. monocytogenes infects the human placenta by invading specialized cells called invasive extravillous trophoblasts (EVTs). Despite being the portal of entry for the placenta, we discovered that EVTs restrict L. monocytogenes intracellular replication by an unknown mechanism. Interestingly, some donors' EVTs were unable to restrict growth. Therefore, we used microarray analysis to compare the transcriptional responses of infected EVTs from human donors that varied in their ability to restrict bacterial replication. A unique set of genes were upregulated only in EVTs that could restrict bacterial replication. One family of genes, the IFIT genes, is involved in innate immune pathways. IFIT genes are known to be upregulated in response to pathogens and also regulate cytokine production. This suggests that antibacterial activity of EVTs is an active process that likely requires proper activation of innate immune pathways. In order to identify and characterize which innate immune pathways actively restrict bacterial growth we have proposed three aims.
In Aim 1, we will use high throughput transcriptomics to discover pathways that are activated and restrict L. monocytogenes replication.
Aim 2 will test the role of IFIT expression in limiting bacterial replication by using a novel human trophoblast progenitor. Finally, in Aim 3 we will determine how a placenta specific virulence factor disrupts innate immune pathways to allow for replication. The knowledge gained from these experiments will guide researchers to rational targets for therapeutics and diagnostics to detect vulnerable populations.
Preterm labor is major source for infant mortality and is often caused by infections. This project will determine how the placenta resists infection and why some people are more susceptible to infection than others. The findings from this project will point to new therapies and help to detect which women are more vulnerable to infections that lead to preterm labor.
| Morrison, Holly A; Lowe, David; Robbins, Jennifer R et al. (2018) In Vivo Virulence Characterization of Pregnancy-Associated Listeria monocytogenes Infections. Infect Immun 86: |
| 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 |
