Zika Induces Human Placental Damage and Inflammation

Abstract

In Brazil, an epidemic of Zika virus (ZIKV) infections was declared in 2015 that coincided with alarming reports of microcephaly in newborns associated with mother infection. Although the virus has placental tropism, changes in the tissue morphology and immunity of infected patients have not yet been elucidated. Here, we investigated the histopathological and ultrastructural changes along with the immunological profile and the BDNF expression in rare placental material. Tissues were obtained in the 2015–2016 Brazilian epidemic, of ten ZIKV-infected patients during pregnancy, five resulting in cases of fetal microcephaly and five non-microcephaly, compared to five non-infected control placentae. Viral antigens were only detected in samples from the ZIKV infected patients. Infected placentae presented histopathological severe damage, while the ultrastructural evaluation showed abnormal organelles, such as clusters of virus-like particles consistent with the ZIKV dimensions. Increased infiltration of CD68 + and TCD8 + cells, expression of MMPs, cytokines (IFN-γ and TNF-α) and other immunological mediators (RANTES/CCL5 and VEGFR-2) confirmed excessive inflammation and vascular permeability dysfunction. An evaluation of BDNF showed a decrease that could modulate neuronal damage in the developing fetus. The placental changes caused by ZIKV are not pathognomonic, however, the data provide evidence that this infection leads to severe placental injury.

Zika virus infection of first trimester trophoblast cells affects cell migration, metabolism and immune homeostasis control

“…The fact that ZIKV decreased BDNF mRNA expression in first trimester cytrophoblast cells suggests a lower availability of BDNF for fetal nervous system development at this early stage. In line with this finding, a recent retrospective study of placentae from pregnant women infected with ZIKV in the 2015–2016 Brazilian epidemic shows lower BDNF immunostaining intensity and a lower number of BDNF expressing cells in decidua and chorionic villi of ZIKV versus control placenta at term (Rabelo et al, 2020). Interestingly, this difference was even larger in placentae from pregnancies that resulted in babies with birth microcephaly compared to those with normal cranial circumference at birth (Rabelo et al, 2020).…”

“…The maternal immune system contributes to limit infections during pregnancy to ensure the survival of the mother and the fetus. In ZIKV infected placenta high CD68+ and TCD8+ cell recruitment as well as higher IFN‐ɣ and TNF‐α expression compared to normal term placenta was reported (Rabelo et al, 2020). However, in contrast to viral infections associated to abortion or preterm delivery, the ZIKV infection does not preclude the progress of pregnancy (Mor et al, 2017; Silasi et al, 2015).…”

“…In general, viral infections during pregnancy display a range of outcome from a spontaneous abortion to fetal infection associate with congenital viral syndromes depending on the virus and the stage of pregnancy (Silasi et al, 2015). An interesting issue of ZIKV infection during pregnancy is the ability of trophoblast cells to survive, while the virus induces an innate and adaptive local immune response (Parker et al, 2020; Rabelo et al, 2020; Santos et al, 2020). This evidence implies that ZIKV might display specific strategies to modulate the trophoblast response to sustain immune homeostasis and pregnancy maintenance, however, these mechanisms are still unknown.…”

Implications of TORCH Diseases in Retinal Development—Special Focus on Congenital Toxoplasmosis

“…CMV may cross the placenta via transcytosis of first-trimester syncytiotrophoblast cells and, in an ex vivo infection decidual organ culture model, HCMV infects invasive cytotrophoblasts, macrophages, and endothelial, decidual and dendritic cells (Weisblum et al, 2011). ZikV has been shown to infect syncytiotrophoblasts, cytotrophoblasts, decidual, and endothelial cells, leading to increased inflammation response, including CD68 and CD8 cell infiltration and cytokines, chemokines and MMP secretion (Rabelo et al, 2020). Additionally, placental cells at birth (mean gestational age 36 weeks) were shown to express AXL, CD209 and TYRO3, which may serve as preferential receptors for the Zika virus entry (Pique-Regi et al, 2020).…”

Innate Immunity Modulation during Zika Virus Infection on Pregnancy: What We Still Need to Know for Medical Sciences Breakthrough

“…Histopathological and immunological studies in placentas have shown that infections by ZIKV lead to an increase in important inflammation markers such as TNF, CCL5, and altered vascular permeability such as metalloproteinases [25]. In addition, in vitro experiments demonstrate that trophoblastic cells become progressively more resistant to infection by ZIKV during pregnancy, partly through the secretion of IFNs [26].…”