Zika Virus Requires the Expression of Claudin-7 for Optimal Replication in Human Endothelial Cells.

Jim Zoladek,Antoine Gessain,Vincent Legros,Pierre-Emmanuel Ceccaldi,Maxime Chazal,Nolwenn Jouvenet,Nathalie Pardigon,Patricia Jeannin,Philippe V Afonso

doi:10.3389/fmicb.2021.746589

Abstract

Zika virus (ZIKV) infection has been associated with a series of neurological pathologies. In patients with ZIKV-induced neurological disorders, the virus is detectable in the central nervous system. Thus, ZIKV is capable of neuroinvasion, presumably through infection of the endothelial cells that constitute the blood-brain barrier (BBB). We demonstrate that susceptibility of BBB endothelial cells to ZIKV infection is modulated by the expression of tight-junction protein claudin-7 (CLDN7). Downregulation of CLDN7 reduced viral RNA yield, viral protein production, and release of infectious viral particles in several endothelial cell types, but not in epithelial cells, indicating that CLDN7 implication in viral infection is cell-type specific. The proviral activity of CLDN7 in endothelial cells is ZIKV-specific since related flaviviruses were not affected by CLDN7 downregulation. Together, our data suggest that CLDN7 facilitates ZIKV infection in endothelial cells at a post-internalization stage and prior to RNA production. Our work contributes to a better understanding of the mechanisms exploited by ZIKV to efficiently infect and replicate in endothelial cells and thus of its ability to cross the BBB.

Highlights

Zika virus (ZIKV) is an arbovirus from the Flaviviridae family, which was first isolated in Uganda in 1947 (Dick et al, 1952)
Since ZIKV neuroinvasion relies on a productive infection of blood-brain barrier (BBB) endothelial cells (Liu et al, 2016; Mladinich et al, 2017; Papa et al, 2017; Richard et al, 2017; Cle et al, 2020), we examined the susceptibility to ZIKV infection of hCMEC/D3 cells
We confirmed that human BBB endothelial cells are susceptible to ZIKV infection (Liu et al, 2010; Mladinich et al, 2017; Papa et al, 2017; Cle et al, 2020)

Summary

Introduction

Zika virus (ZIKV) is an arbovirus from the Flaviviridae family, which was first isolated in Uganda in 1947 (Dick et al, 1952). It was initially disregarded as only sporadic and mild cases were reported. With the virus outbreaks in the Pacific Islands and the Americas in 2015, ZIKV received widespread attention These outbreaks were associated with neurological pathologies, such as Guillain-Barré syndrome (Cao-Lormeau et al, 2016), congenital microcephaly (Cauchemez et al, 2016), meningoencephalitis (Carteaux et al, 2016), and myelitis (Mecharles et al, 2016). During ZIKV-induced neurological disorders, the virus is detected in the central nervous system (CNS), and viral RNA can be amplified from the cerebrospinal fluid of infected patients (Roze et al, 2016).

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