Differential Type 1 IFN Gene Expression in CD14+ Placenta Cells Elicited by Zika Virus Infection During Pregnancy

Nicole N Haese,Jessica L Smith,Alec J Hirsch,Kosiso Onwuzu,Antonio E Frias,Nicholas Kreklywich,Hannah Smith,Terry K Morgan,Michael Denton,Benjamin N Bimber,Victoria H J Roberts,Craig N Kreklywich,Daniel N Streblow,Aaron D Streblow

doi:10.3389/fviro.2021.783407

Abstract

Zika virus (ZIKV) is an arthropod-borne Flavivirus that can also be transmitted vertically from infected mother to fetus. Infection of the fetus during pregnancy can lead to congenital malformations and severely impact fetal brain development causing a myriad of diseases now labeled Congenital Zika Syndrome (CZS). The mechanisms by which ZIKV crosses the placenta into the fetal circulation and the extent of ZIKV-induced changes remain unclear. We have previously shown that ZIKV infection of pregnant rhesus macaques results in abnormal oxygen transport across the placenta which may promote uterine vasculitis and placental villous damage. Changes in immune cell frequencies and activation status were also detected, as were distinct changes in the proportions of CD14+ cell subsets with an altered ratio of classical to non-classical CD14+ monocyte cells in both the maternal decidua and placental villous from ZIKV-infected animals compare to uninfected controls. In the current study, we performed single cell RNA sequencing on CD14+ cells isolated from the decidua of animals that were ZIKV infected at 31, 51, or 115 days of gestation (where term is ~168 days) compared to pregnant, time-matched uninfected controls. Bioinformatic analysis identified unique transcriptional phenotypes between CD14+ cells of infected and uninfected animals suggesting a distinct and sustained difference in transcriptomes between infected and uninfected CD14+ cells derived from the decidua. The timing of ZIKV infection had no effect on the CD14+ cell transcriptional profiles. Interestingly, ZIKV infection caused changes in expression of genes in pathways related to cellular stress and metabolism as well as immune response activation. Type 1 interferon response genes (ISGs) were among those that were differentially expressed following infection and these included members of the ISG12 family, IFI27 and IFI6. These ISGs have been recently described as effectors of the IFN response to flaviviruses. Supplementing our animal findings, in CD14+ cells isolated from human placenta, ZIKV infection similarly induced the expression of IFI27 and IFI6. Overall, our results showed that ZIKV infection during pregnancy induces the stable expression of antiviral genes within CD14+ cells of the placenta, which may provide an immune shield to protect the placenta from further infection and damage.

Highlights

Zika virus (ZIKV) is a flavivirus most commonly transmitted by the bite from an infected Aedes mosquito
The rhesus macaque model of in utero ZIKV infection recapitulates many of the hallmarks of the human disease caused by this neurotropic flavivirus including fetal neuropathy and demise
We previously showed that ZIKV infection in Rhesus macaques during pregnancy induces placental damage associated with increased vascular damage that leads to altered nutrient perfusion across placental membranes, as well as increased inflammation and remodeling [8]

Summary

Introduction

Zika virus (ZIKV) is a flavivirus most commonly transmitted by the bite from an infected Aedes mosquito. In the most recent epidemic, evidence indicates that ZIKV can cause neurological sequelae such as Guillain-Barre Syndrome in adults [1, 2]. Prenatal ZIKV exposure was first associated with an increased risk for severe microcephaly in infants [3, 4]. It is clear that infection during pregnancy can result in a range of presentations with variable severity referred to as Congenital Zika Syndrome (CZS), divided into mutually exclusive categories: [1] brain abnormalities and/or microcephaly and [2] neural tube defects, eye abnormalities, or consequences of central nervous system dysfunction among fetuses or infants without evidence of other brain abnormalities or microcephaly [3, 5]. Nearly half of the infants exposed to Zika in utero manifest abnormalities at birth or have symptoms during the first year of life [4, 7]

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