Human Endometrial Stromal Cells Are Highly Permissive To Productive Infection by Zika Virus

Abstract

Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy.

p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection

“…TAM receptors, including TYRO3, AXL and MERTK, are the putative entry receptors for some flaviviruses (Miner et al, 2016) and ZIKV is known to utilize these cell surface receptors to infect various cell types (Pagani et al, 2017; Richard et al, 2017; Savidis et al, 2016). To determine if primary Müller cells are permissive to ZIKV infection, we first examined the expressions of TAM receptors by quantitative PCR (qPCR).…”

Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network

“…In vivo and in vitro studies have shown that ZIKV cell tropism may reflect the expression pattern of virus co-receptors, such as AXL, a member of TAM receptor family, either directly, or as a signaling molecule that may modulate the type I-interferon receptor (IFNAR) pathway (Hamel et al, 2015; Nowakowski et al, 2016; Meertens et al, 2017; Pagani et al, 2017; Tabata et al, 2016; Richard et al, 2017). TIM1 has also been reported to act as a co-receptor (Hamel et al, 2015; Tabata et al, 2016).…”

The E3 ligase TRIM56 is a host restriction factor of Zika virus and depends on its RNA-binding activity but not miRNA regulation, for antiviral function

“…To this end, we investigated the impact of TRIM56 on ZIKV infection in 293T-derived cells deficient in Dicer expression thus lacking the biogenesis of miRNAs [33]. First, we confirmed the Dicer deficiency phenotype in two clonal cell lines (referred to as No-Dice (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and ) by showing the absence of miR-92a and miR-21 expression, as opposed to control 293T (referred to as 293T-WT) cells ( Fig 6A). It should be noted that total small RNA deep sequencing analysis had shown these two Dicer-knockout 293T cell lines were deficient in miRNA expression globally, as opposed to 293T-WT cells, in a previous study [33].…”

“…Human embryonic kidney (HEK) 293, HeLa, SV40 T antigen-transformed human fetal glial cell line SVGA (a gift from Santosh Kumar, University of Tennessee Health Science Center (UTHSC)), human neuroblastoma SK-N-SH (kindly provided by Francesca-Fang Liao, UTHSC), human hepatoma cell lines Huh7 and HLCZ01 (kindly provided by Haizhen Zhu, Hunan University, China) [32], SV40 T antigen-immortalized human hepatocyte PH5CH8, African green monkey kidney cell lines Vero and BSC-1, murine embryonic fibroblasts (MEFs), mouse fibroblast cell line L929, mouse hepatoma Hepa1-6 cells, and mosquito C6/36 cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 U/ml of penicillin, and 100 μg/ml of streptomycin. HEK293T and its clonal derivatives deficient in Dicer expression, No-Dice (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and No-Dice (4-25) [33], were kindly provided by Bryan Cullen (Duke University Medical Center).…”

“…. [11,[16][17][18]. Further studies on tissue tropism of the virus and factors regulating viral replication in and host responses of susceptible cell types are warranted, as they will yield novel insights into mechanisms of ZIKV pathogenesis and may identify therapeutic targets.…”