Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface

Abstract

During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.

Keywords: decidua; innate immunity; trophoblast; uterine-placental interface; vertical transmission.

Figure 1

Possible infection and vertical transmission route at the maternal-fetal interface. Illustration representing the anchoring placenta villi of early pregnancy, with onset of maternal blood circulation bathing the intervillous space. SCT-blood interface represents the SCT barrier exposed to maternal blood and immune cells. EVT-decidua interface represents the interface between EVT and maternal decidua cells. Major cell types of placenta trophoblast and decidua from Vento-Tormo et al. (10) are represented. SCT, syncytiotrophoblast; VCT, villous cytotrophoblast; EVT, extravillous trophoblast; DC, dendritic cell; dNK, decidua Natural killer cells; dM, decidua macrophages; HB, Hofbauer cell; PV, perivascular cells; FcRN, neonatal Fc receptor. Figure is created by BioRender.com.

Figure 2

Toll-like receptors and potential inflammatory response at the SCT-blood interface. Predominant TLRs found in the human placenta from early and term pregnancies. TLR2 and TLR4 are expressed in human placenta SCT, VCT, and in HB cells. Infiltration of infected maternal blood, infected immune cells, or release of pathogenic determinant such lipopolysaccharide (LPS), peptidoglycan, or parasite materials such as hemozoin or GPI (glycosylphosphatidylinositol) into the IVS will activate TLR-mediated signaling, leading to the production of a wide range of cytokines and chemokines. Severe infection is characterized by massive immune cell infiltration including monocytes and neutrophils from systemic circulation and overproduction of inflammatory cytokines upon TLR activation. This may lead to SCT inflammation and damage. SCT also secretes antimicrobial peptides as innate immune mechanisms. Figure is created by BioRender.com.

Figure 3

Toll-like receptors and potential inflammatory response at the decidua. Predominant TLRs found in the human placenta from early and term pregnancies. TLR2 and TLR4 are expressed in EVT. dM and dNK also express a wide range of TLR families, where stimulation of TLR agonists lead to the production of a variety of cytokines and chemokines. Infiltration of infected cells and release of PAMPs in the decidua, which will activate TLR-mediated signaling. Overproduction of inflammatory cytokines at the decidua may lead to local inflammation. Figure is created by BioRender.com.

Figure 4

Dotplot representing normalized and log transformed values expression of TLR (TLR1-10), NLR genes (NOD1, NOD2, NLRP1, NLRP3) and IDO1 at steady state in early pregnancy from Vento-Tormo et al. (10). Origin of cell types from placenta (red), decidua (blue), and maternal blood (green) are labeled as differences in font color. Dot size represents the fraction of cells from a certain cluster expressing a gene and color scale represents normalized log transformed expression of the gene in that cluster. dS, decidua stroma; F, fibroblast; MO, monocyte; Endo, endothelial; Epi, epithelial; SCT, syncytiotrophoblast; VCT, villous cytotrophoblast; EVT, extravillous trophoblast; DC, dendritic cell; dNK, decidua Natural killer cells; dM, decidua macrophages; HB, Hofbauer cell; PV, perivascular cells. Figure is created by BioRender.com.