Zika Virus–Infected Decidual Cells Elicit a Gestational Age–Dependent Innate Immune Response and Exaggerate Trophoblast Zika Permissiveness: Implication for Vertical Transmission

Abstract

Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.

Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner

“…We did not observe IFN-λ responsiveness in a human decidualized endometrial cell line, but decidual cells respond to IFN-λ in other human cell culture models, including explants and organoids (8,9). Differences in decidual responsiveness have been noted from cell models taken at different times in gestation (37) and could explain the lack of IFN-λ responsiveness we observed in a decidual cell line.…”

Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal-fetal interface

“…The decidua also responds to microbial infections via the release of additional cytokines that function in innate defense (Barber et al, 2005;Guzeloglu-Kayisli et al, 2020;Qiu et al, 2009). However, in many cases, these studies were performed on tissue explants that were multicellular in nature, thus preventing an assessment of the contributions of cytokine release from distinct cell types.…”

“…Studies of tissue explants and histopathologic analysis of the placenta suggest that the decidua and chorionic villi have differing roles in the pathogenesis of relevant infections. The decidua may be a primary site of replication for several microorganisms associated with congenital disease, including cytomegalovirus (CMV) (McDonagh et al, 2006; Pereira et al, 2003; Weisblum et al, 2011), Zika virus (ZIKV) (Guzeloglu-Kayisli et al, 2020; Platt et al, 2018; Weisblum et al, 2017), and Listeria monocytogenes (Rizzuto et al, 2017), suggesting it may serve as a reservoir for these infections. By contrast, the placenta is largely resistant to infections and possesses a number of intrinsic mechanisms of innate defense.…”

Infections at the maternal–fetal interface: an overview of pathogenesis and defence

“…For example, decidual stromal cell function is altered with co-culture with macrophages 42 , dendritic cells and NK cells in a prostaglandin-dependent manner 43 . Moreover, the response of decidual stromal cells to pathogen stimulation is different from that of endometrial stromal cells 44 – 46 , suggesting that the microenvironment of the placenta has a role in innate immune defences. Decidual explants have been used to demonstrate that CD8 + effector memory T cells and NK cells can regulate decidual stromal CMV 47 and herpes simplex virus (HSV) 48 infections.…”