Research Article: Placental Syncytium Forms a Biophysical Barrier against Pathogen Invasion

Date Published: December 12, 2013

Publisher: Public Library of Science

Author(s): Varvara B. Zeldovich, Casper H. Clausen, Emily Bradford, Daniel A. Fletcher, Emin Maltepe, Jennifer R. Robbins, Anna I. Bakardjiev, Michael R. Wessels.


Fetal syncytiotrophoblasts form a unique fused multinuclear surface that is bathed in maternal blood, and constitutes the main interface between fetus and mother. Syncytiotrophoblasts are exposed to pathogens circulating in maternal blood, and appear to have unique resistance mechanisms against microbial invasion. These are due in part to the lack of intercellular junctions and their receptors, the Achilles heel of polarized mononuclear epithelia. However, the syncytium is immune to receptor-independent invasion as well, suggesting additional general defense mechanisms against infection. The difficulty of maintaining and manipulating primary human syncytiotrophoblasts in culture makes it challenging to investigate the cellular and molecular basis of host defenses in this unique tissue. Here we present a novel system to study placental pathogenesis using murine trophoblast stem cells (mTSC) that can be differentiated into syncytiotrophoblasts and recapitulate human placental syncytium. Consistent with previous results in primary human organ cultures, murine syncytiotrophoblasts were found to be resistant to infection with Listeria monocytogenes via direct invasion and cell-to-cell spread. Atomic force microscopy of murine syncytiotrophoblasts demonstrated that these cells have a greater elastic modulus than mononuclear trophoblasts. Disruption of the unusually dense actin structure – a diffuse meshwork of microfilaments – with Cytochalasin D led to a decrease in its elastic modulus by 25%. This correlated with a small but significant increase in invasion of L. monocytogenes into murine and human syncytium. These results suggest that the syncytial actin cytoskeleton may form a general barrier against pathogen entry in humans and mice. Moreover, murine TSCs are a genetically tractable model system for the investigation of specific pathways in syncytial host defenses.

Partial Text

Intrauterine infection is associated with pregnancy complications such as preterm labor [1], which affects 10% of all live births [2]. All of the hematogenous placental microbes have at least partially intracellular life cycles [3]. Among these is L. monocytogenes, a facultative intracellular bacterium that causes foodborne disease in humans and other mammals. The relative risk of listeriosis is ∼115-fold higher in pregnant women compared to non-pregnant women of reproductive age [4]. The Centers for Disease Control reported 1,651 cases in the US during 2009–2011, of these 227 (14%) were pregnancy-associated [5]. L. monocytogenes triggers preterm labor and spreads to the fetus; the neonatal case-fatality rate is 22–45% [6]–[10]. Thus, pregnancy-associated listeriosis is a severe but rare disease. However, L. monocytogenes is ingested frequently by healthy adults [11]. Thus, it seems reasonable to hypothesize that the maternal-fetal interface forms an extremely effective barrier against infection. Perhaps the etiology of preterm labor is multifactorial even in cases of documented intrauterine infection. Indeed, recent evidence suggests that a combination of host genetic factors and bacterial products triggers preterm labor [12].

We adapted the mouse system of differentiated mTSCs to study placental defenses against infection. We show that multinucleated fused syncytiotrophoblasts have a greater elastic modulus than mononuclear trophoblasts, and that actin contributes to this phenotype. We present evidence that disruption of the actin cytoskeleton decreases the elastic modulus of syncytiotrophoblasts and increases bacterial spread into the syncytium in both mouse and human. Taken together, these findings suggest that the biophysical properties of the syncytium, a tissue unique to the placenta, may contribute to host defense mechanisms and protect the fetus.




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