Participation of Extracellular Vesicles from Zika-Virus-Infected Mosquito Cells in the Modification of Naïve Cells’ Behavior by Mediating Cell-to-Cell Transmission of Viral Elements

Abstract

To date, no safe vaccine or antivirals for Zika virus (ZIKV) infection have been found. The pathogenesis of severe Zika, where host and viral factors participate, remains unclear. For the control of Zika, it is important to understand how ZIKV interacts with different host cells. Knowledge of the targeted cellular pathways which allow ZIKV to productively replicate and/or establish prolonged viral persistence contributes to novel vaccines and therapies. Monocytes and endothelial vascular cells are the main ZIKV targets. During the infection process, cells are capable of releasing extracellular vesicles (EVs). EVs are mediators of intercellular communication. We found that mosquito EVs released from ZIKV-infected (C6/36) cells carry viral RNA and ZIKV-E protein and are able to infect and activate naïve mosquito and mammalian cells. ZIKV C6/36 EVs promote the differentiation of naïve monocytes and induce a pro-inflammatory state with tumor necrosis factor-alpha (TNF-α) mRNA expression. ZIKV C6/36 EVs participate in endothelial vascular cell damage by inducing coagulation (TF) and inflammation (PAR-1) receptors at the endothelial surface of the cell membranes and promote a pro-inflammatory state with increased endothelial permeability. These data suggest that ZIKV C6/36 EVs may contribute to the pathogenesis of ZIKV infection in human hosts.

Extracellular Vesicles in Viral Infections of the Nervous System

“…The ZIKV C6/36 EVs can lead to the differentiation of naïve monocytes and induce the expression of pro-inflammatory cytokines. Additionally, the ZIKV C6/36 EVs have also been shown to cause damage to vascular endothelial cells and induce inflammation, leading to increased BBB endothelial permeability [ 91 ]. Another study demonstrated that ZIKV could infect human astrocytes derived from fetal brains and that neurons were less susceptible to ZIKV infection compared with astrocytes.…”

Extracellular Vesicles in Viral Spread and Antiviral Response

“…Exosomes from C6/36 mosquito cells infected with Zika virus (ZIKV) may also modify host cells responses and contribute to the pathogenesis of ZIKV infection in humans. These exosomes induced a pro-inflammatory state and participated in endothelial vascular cell damage by inducing coagulation, inflammation and endothelial permeability [ 85 ].…”

Extracellular Vesicles in Viral Replication and Pathogenesis and Their Potential Role in Therapeutic Intervention

“…Interestingly, there are viruses that not only hijack host EVs, but also boost the production of EVs such as in ZIKA virus (ZIKV). EVs released from ZIKV-infected (C6/36) cells carry viral RNA and ZIKV-E protein that can trigger monocyte activation to induce mRNA expression of TNF-α [145]. ZIKV-infected cells have incrementation in their neutral Sphingomyelinase (nSMase)-2/SMPD3 gene expression and activity, which provokes the production and excretion of EVs in neurons.…”