Innate Immune Response to Viral Infections at the Maternal-Fetal Interface in Human Pregnancy

Abstract

The placenta, the first and largest organ to develop after conception, not only nurtures and promotes the development of the conceptus, but, it also functions as a barrier against invading pathogens. Early phases of pregnancy are associated with expansion of specific subsets of Natural Killer cells (dNK) and macrophages (dMφ) at the maternal uterine mucosa, the basal decidua. In concert with cells of fetal origin, dNK cells, and dMφ orchestrate all steps of placenta and fetus development, and provide the first line of defense to limit vertical transmission. However, some pathogens that infect the mother can overcome this protective barrier and jeopardize the fetus health. In this review, we will discuss how members of the classical TORCH family (Toxoplasma, Other, Rubella, Cytomegalovirus, and Herpes simplex virus) and some emerging viruses (Hepatitis E virus, Zika virus, and SARS-CoV2) can afford access to the placental fortress. We will also discuss how changes in the intrauterine environment as a consequence of maternal immune cell activation contribute to placental diseases and devastating pregnancy outcomes.

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…Toxoplasma, Rubella, Cytomegalovirus, and HSV (TORCH pathogens) are all known for crossing the maternal-fetal interface. 123 These pathogens reach the fetal compartment through hematogenous or decidual spread, leading to congenital syndromes or high case fatality. 124 Blood monocytes and tissue macrophages have been shown to be a favorable cellular target for several pathogens known be transmitted vertically such as Zika virus.…”

“…127,128 Indeed, innate immune cells at the maternal-fetal interface provide the first line of defense against vertical transmission of viral pathogens. 123 Additionally, placental trophoblasts express a repertoire of PRRs including TLRs (3,7,8,9) and secrete type III interferons leading to the induction of interferon-stimulated genes (ISG). 123,129,130 In vitro analyses show that in response to TLR activation, decidual macrophages secrete both pro-inflammatory and antiinflammatory cytokines.…”

“…123 Additionally, placental trophoblasts express a repertoire of PRRs including TLRs (3,7,8,9) and secrete type III interferons leading to the induction of interferon-stimulated genes (ISG). 123,129,130 In vitro analyses show that in response to TLR activation, decidual macrophages secrete both pro-inflammatory and antiinflammatory cytokines. This serves as an attempt to maintain fetal tolerance while responding to microbial challenge.…”

“…141 Zika virus (ZIKV) is a flavivirus that can be transmitted via blood transfusion, sexual contact, or mosquito bite. ZIKV is known for its ability to surmount intrinsic defense mechanisms of the placenta allowing it to reach 10% of developing fetuses 123 resulting in adverse birth defects such as microcephaly. 142 CD14 + CD16 + monocytes are the main target of ZIKV infection.…”

“…Toxoplasma, Rubella, Cytomegalovirus, and HSV (TORCH pathogens) are all known for crossing the maternal‐fetal interface 123 . These pathogens reach the fetal compartment through hematogenous or decidual spread, leading to congenital syndromes or high case fatality 124 .…”