Host-Viral Interactions at the Maternal-Fetal Interface. What We Know and What We Need to Know

Abstract

In humans, the hemochorial placenta is a unique temporary organ that forms during pregnancy to support fetal development, gaseous exchange, delivery of nutrition, removal of waste products, and provides immune protection, while maintaining tolerance to the HLA-haploidentical fetus. In this review, we characterize decidual and placental immunity during maternal viral (co)-infection with HIV-1, human cytomegalovirus (HCMV), and Zika virus. We discuss placental immunology, clinical presentation, and epidemiology, before characterizing host susceptibility and cellular tropism, and how the three viruses gain access into specific placental target cells. We describe current knowledge on host-viral interactions with decidual and stromal human placental macrophages or Hofbauer cells, trophoblasts including extra villous trophoblasts, T cells, and decidual natural killer (dNK) cells. These clinically significant viral infections elicit both innate and adaptive immune responses to control replication. However, the three viruses either during mono- or co-infection (HIV-1 and HCMV) escape detection to initiate placental inflammation associated with viral transmission to the developing fetus. Aside from congenital or perinatal infection, other adverse pregnancy outcomes include preterm labor and spontaneous abortion. In addition, maternal HIV-1 and HCMV co-infection are associated with impaired fetal and infant immunity in postnatal life and poor clinical outcomes during childhood in exposed infants, even in the absence of vertical transmission of HIV-1. Given the rapidly expanding numbers of HIV-1-exposed uninfected infants and children globally, further research is urgently needed on neonatal immune programming during maternal mono-and co-infection. This review therefore includes sections on current knowledge gaps that may prompt future research directions. These gaps reflect an emerging but poorly characterized field. Their significance and potential investigation is underscored by the fact that although viral infections result in adverse consequences in both mother and developing fetus/newborn, antiviral and immunomodulatory therapies can improve clinical outcomes in the dyad.

Keywords: HIV-1; Hofbauer cell; Zika; cytotrophoblast; human cytomegalovirus; natural killer cell; placenta; vertical transmission.

FIGURE 1 |

(A–E) Anatomical illustration of the placenta. The placenta plays a critical role in a successful pregnancy and fetal development. Chorionic villi (magnified) support contact with the maternal circulation. Individual cells and their respective locations in the decidua (natural killer, T, and macrophage cells) and villi (Hofbauer cells) are illustrated. Cytotrophoblast cells are found in the decidua basalis and in placental villi, while syncytiotrophoblast cells line placental villi. This interface facilitates delivery of nutrients and oxygen from endometrial arteries. During maternal infection, pathogens may breach the trophoblast layer and migrate toward the fetal side of the interface. HCs change their phenotype during gestation. Activated HCs are abundant in early pregnancy and become regulatory thereafter until parturition. (B–E) Represents the phenotypic changes that Hofbauer cells undergo during gestation.

FIGURE 2 |

HCs exhibit reduced ability to replicate HIV-1. (A) HCs (Green) sequester virus and may serve as protective reservoirs to permit intracellular neutralization in virus-containing compartments (VCCs in Blue). (B) Endogenous production and secretion of immunoregulatory cytokines such as IL-10 and TGF-β by HCs are important in not only supporting tolerance to the haploidentical fetus but also limiting inflammation and viral replication during maternal HIV-1 infection.

FIGURE 3 |

Putative mechanism of HIV-1 infection of cytotrophoblasts. 1) Cell-associated HIV-1 in the maternal circulation either antibody coated, or antibody free reach the maternal-fetal interface of the placenta. 2) HIV-1 infection is restricted to CD4+ CCR5+ tropic cells. However, endogenous retroviral fusion protein, syncytin expressed on trophoblast cells may facilitate entry of HIV-1 via membrane fusion. 3) HIV-1 infection in cytotrophoblasts (CTBs) may lead to production of pseudotyped HIV-1 (Blue virion), and CD4+ tropic HIV-1 (Red virion). 4) HIV-1 transmission to the fetus may be offset by CTBs and innate antiviral responses. Hofbauer cells (HCs; Purple cell) may be targeted by HIV-1 infection (gray indicates HIV-1-infected HC).

FIGURE 4 |

HCMV transmission in chorionic villi. (A) In the physiologic state, maternal IgG binds FcRn in endosomes and can take different paths: either recycle (going back to the surface) or undergo transcytosis toward the basal membrane and bind to cells that express FcR. (B) HCMV Infection. The HCMV-infected virion disrupts trophoblast cells and forms HCMV IgG immune complexes that undergo FcR-mediated transcytosis. The HCMV-IgG immune complex can go on to infect HCs, fibroblasts, fetal capillaries. HCMV may be able to increase the expression of FcR (59). CTBs are important sites for placental HCMV infection, most likely transmit virus to the fetus, and HCMV could disseminate to the placenta by co-opting the receptor-mediated transport pathway for IgG.

FIGURE 5 |

Putative mechanisms of HCMV induced intracellular damage in trophoblast cells. 1) The exact mechanisms by which HCMV infects trophoblast cells remain unclear (refer to Figure 4), however, molecular mechanisms by which HCMV causes intracellular damage are well documented. 2) HCMV glycoprotein US3 directly binds to both HLA-C and HLA-G within the endoplasmic reticulum (ER) and blocks transportation of MHC molecules only partially downregulating HLA-C upon HCMV infection of primary EVT cells. 3) Cytoplasmic proteins are constantly monitored by proteosome processing and peptides are retrograde transported to the ER through transporter TAP to be loaded onto the MHC. 4) HCMV glycoprotein US6 inhibits the TAP, and the cytoplasmic peptide-including HCMV derived peptide are unable to enter the ER. 5) Because of reduced expression of MHC class I molecules on HCMV-infected CTBs, cytolytic T cell recognition is impaired. 6) NK cell-mediated cytolytic killing of HCMV-infected stromal cells may result in placental damage.

FIGURE 6 |

Zika virus non-structural protein impairs innate immune activation. (A) Proteolytic cleavage of zika virus polyprotein. Structural proteins form capsids (C), glycoprotein precursor premembrane (PreM), and envelope proteins (E). Structural proteins are indicated in blue, non-structural proteins are shown in orange. A brief description of each essential non-structural protein are indicated by the arrows. (B) 1) ZIKV RNA is recognized by the retinoic acid-inducible gene I (RIG-1), 2) leading to subsequent activation of IFN regulatory factors such as NF-kB and IRF3. 3) These activate the production of type I and III IFNs, which are mediated by the JAK-STAT signaling pathway to induce cells into an antiviral state. 4) ZIKV non-structural protein NS5 can antagonize JAK-STAT signaling, evading gene activation, and blocking cellular conversion into an antiviral state. 5) NS1, NS4A, NS4B impair type-I IFN responses.