Placental Pathology of Zika Virus: Viral Infection of the Placenta Induces Villous Stromal Macrophage (Hofbauer Cell) Proliferation and Hyperplasia

Abstract

Context.-The placenta is an important component in understanding the fetal response to intrauterine Zika virus infection, but the pathologic changes in this organ remain largely unknown. Hofbauer cells are fetal-derived macrophages normally present in the chorionic villous stroma. They have been implicated in a variety of physiological and pathologic processes, in particular involving infectious agents.Objectives.-To characterize the fetal and maternal responses and viral localization in the placenta following Zika virus transmission to an 11 weeks' gestation fetus. The clinical course was notable for prolonged viremia in the mother and extensive neuronal necrosis in the fetus. The fetus was delivered at 21 weeks' gestation after pregnancy termination.Design.-The placenta was evaluated by using immunohistochemistry for inflammatory cells (macrophages/ monocytes [Hofbauer cells], B and T lymphocytes) and proliferating cells, and an RNA probe to Zika virus. The fetal brain and the placenta were previously found to be positive for Zika virus RNA by reverse transcriptionpolymerase chain reaction.Results.-The placenta demonstrated prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells. The degree of Hofbauer cell hyperplasia gave an exaggerated immature appearance to the villi. No acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhages were present. An RNA probe to Zika virus was positive in villous stromal cells, presumably Hofbauer cells.Conclusions.-Zika virus placental infection induces proliferation and prominent hyperplasia of Hofbauer cells in the chorionic villi but does not elicit villous necrosis or a maternal or fetal lymphoplasmacellular or acute inflammatory cell reaction.

Zika virus infection of Hofbauer cells

“…7,8 The human placenta has innate defenses that must be evaded or infiltrated for a virus to cause such severe outcomes in a short inoculation period. [9][10][11] Unlike all other members of the Flavivirus genus, ZIKV infection is capable of this feat and compromises the integrity of the maternal-fetal barrier. Early cases exhibited intraplacental calcifications, fibrin deposits, and sclerosis, all of which are indicative of a fetus with poor uteroplacental flow, and at increased risk of adverse outcomes.…”

Zika Virus Infection at Different Pregnancy Stages: Anatomopathological Findings, Target Cells and Viral Persistence in Placental Tissues

“…Although positivity in fetal endothelium and maternal leukocytes (Ritter et al, 2017), and in decidual cells, CTBs and mesenchymal cells of chorionic villi (Rabelo et al, 2018) in a few first trimester placentas has also been reported, we speculate that maternal or other fetal cells may be infected only transiently. In support of this hypothesis, studies of natural ZIKV infections using either IHC or in situ hybridization analysis (ISH) have also reported that HCs were the most frequently observed infected cells (Bhatnagar et al, 2017;Martines et al, 2016a;Noronha et al, 2016;Rosenberg et al, 2017).…”

Congenital Zika syndrome: Pitfalls in the placental barrier

“…Necropsy revealed that the fetus had profound abnormalities in the CNS, yet samples of placenta showed "no evidence of ongoing, remote, acute, or chronic villitis or intervillositis". 30 This suggests that, in some cases, ZIKV can access the fetal CNS without provoking a significant inflammatory reaction in the placenta. However, in 4 cases of congenital ZIKV infection that resulted in fetal/neonatal loss, there was evidence of systemic vascular pathology affecting multiple organ systems, yet ZIKV RNA was found exclusively in the brain and placenta.…”

“…One case study followed a fetus who developed an intrauterine ZIKV infection at 11 weeks' gestation, later aborted at 21 weeks. Necropsy revealed that the fetus had profound abnormalities in the CNS, yet samples of placenta showed “no evidence of ongoing, remote, acute, or chronic villitis or intervillositis” . This suggests that, in some cases, ZIKV can access the fetal CNS without provoking a significant inflammatory reaction in the placenta.…”