UCSF

Placental infections can lead to severe pregnancy complications as well as infection of the fetus with significant morbidity and mortality. Among pathogens that can cross the maternal-fetal barrier is the facultative intracellular bacterium, Listeria monocytogenes, which is highly amenable to experimental analysis. We used this model pathogen to study infection dynamics at the maternal-fetal interface.

Using human placental organ cultures, we found that the syncytiotrophoblast -- which constitutes most of the placental surface and is bathed in maternal blood in vivo -- is highly resistant to L. monocytogenes infection. We hypothesize this resistance to be a result of the unique biophysical characteristics of the syncytium. We present our preliminary data in support of this hypothesis and the development of the mouse trophoblast model system that will be used to study this further.

We next show that extravillous cytotrophoblasts (EVT) -- which anchor the placenta in the decidua (uterine lining) -- serve as the primary portal of entry for pathogens into the placenta. However, they restrict bacterial growth and represent another barrier to infection. Using primary human trophoblast cell culture, we characterized the intracellular fate of L. monocytogenes in EVT. We found that these cells entrap bacteria in vacuolar compartments where they are degraded. Specifically, bacteria remain confined to acidified vacuoles and co-localize with LAMP1, consistent with bacterial degradation in lysozomes. Further studies show that autophagy is not responsible for this bacteriocidal phenotype of EVT, though reactive nitrogen species and cationic microbial peptides may play a role. Efforts to further discern the bacterial killing mechanism are underway. Specifically, we are in the process of defining the global EVT transcriptional response to infection. We hope to also use these data to study the role of EVT in the development of pregnancy complications.

Our studies show that the placenta has evolved multiple mechanisms to resist pathogen infection. The syncytium is a robust barrier to invasion by blood-borne pathogens, while EVT have innate cellular defense mechanisms to restrict pathogens. Our understanding of these novel placental barriers to infection may help develop new paradigms in the diagnosis and treatment of pregnancy complications.