Characterization of zika virus infection of human fetal cardiac mesenchymal stromal cells

Abstract

Zika virus (ZIKV) is a single-stranded RNA virus belonging to the family Flaviviridae. ZIKV predominantly enters cells using the TAM-family protein tyrosine kinase receptor AXL, which is expressed on a range of cell types, including neural progenitor cells, keratinocytes, dendritic cells, and osteoblasts. ZIKV infections have been associated with fetal brain damage, which prompted the World Health Organization to declare a public health emergency in 2016. ZIKV infection has also been linked to birth defects in other organs. Several studies have reported congenital heart defects (CHD) in ZIKV infected infants and cardiovascular complications in adults infected with ZIKV. To develop a better understanding of potential causes for these pathologies at a cellular level, we characterized ZIKV infection of human fetal cardiac mesenchymal stromal cells (fcMSCs), a cell type that is known to contribute to both embryological development as well as adult cardiac physiology. Total RNA, supernatants, and/or cells were collected at various time points post-infection to evaluate ZIKV replication, cell death, and antiviral responses. We found that ZIKV productively infected fcMSCs with peak (~70%) viral mRNA detected at 48 h. Use of an antibody blocking the AXL receptor decreased ZIKV infection (by~50%), indicating that the receptor is responsible to a large extent for viral entry into the cell. ZIKV also altered protein expression of several mesenchymal cell markers, which suggests that ZIKV could affect fcMSCs' differentiation process. Gene expression analysis of fcMSCs exposed to ZIKV at 6, 12, and 24 h post-infection revealed up-regulation of genes/pathways associated with interferonstimulated antiviral responses. Stimulation of TLR3 (using poly I:C) or TLR7 (using Imiquimod) prior to ZIKV infection suppressed viral replication in a dose-dependent manner. Overall, fcMSCs can be a target for ZIKV infection, potentially resulting in CHD during embryological development and/or cardiovascular issues in ZIKV infected adults.

The role of glial cells in Zika virus‐induced neurodegeneration

“…ZIKV can infect several body sites, including the eyes, cardiac tissue, the gastrointestinal (GI) system, reproductive tract, placenta, and central nervous system (CNS) (Figure 1) (Gasco & Muñoz‐Fernández, 2020; Rossi et al, 2020; Ryan et al, 2021; Zafar et al, 2021). The most common symptoms of acute ZIKV infection include fever, headaches, myalgias, rash, and conjunctivitis.…”

Neuroanatomical abnormalities in a nonhuman primate model of congenital Zika virus infection

“…Since the onset of the ZIKV pandemic that began in 2015, a number of studies have revealed important information about how ZIKV targets specific cell types and proteins within the central nervous system (for reviews Khaiboullina et al, 2019 ; Sutarjono, 2019 ). The neurotropism of the virus may result from ZIKV using AXL, a tyrosine kinase receptor important in modulating the innate immune system ( Rothlin et al, 2007 ; Hafizi and Dahlbäck, 2006 ), to enter the brain ( Meertens et al, 2017 ; Rossi et al, 2020 ; Nowakowski et al, 2016 ). Single-cell RNA sequencing analyses have demonstrated that AXL is highly expressed in radial glia, endothelial cells, microglia, and astrocytes in the developing human cortex ( Nowakowski et al, 2016 ).…”

Identification of novel anti-ZIKV drugs from viral-infection temporal gene expression profiles

“…Sendai virus, vesicular stomatitis virus, WNV, Enterovirus 71, influenza virus) [ 56 ]. TLR7 agonist Imiquimod, also identified in this work, suppresses ZIKV replication in human fetal cardiac mesenchymal stromal cells in a dose-dependent manner [ 40 ]. Known anti-ZIKV agents chloroquine and hydroxychloroquine repress ssRNAs-mediated activation of TLR7 signalling and the production of IFN-α [ 57 ].…”