**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**

#### **Pedro Pablo Martínez-Rojas 1, Elizabeth Quiroz-García 1, Verónica Monroy-Martínez 1, Lourdes Teresa Agredano-Moreno 2, Luis Felipe Jiménez-García 2 and Blanca H. Ruiz-Ordaz 1,\***


agredano-moreno@ciencias.unam.mx (L.T.A.-M.); luisfelipe\_jimenez@ciencias.unam.mx (L.F.J.-G.) **\***Correspondence:bhro@unam.mxbhro@iibiomedicas.unam.mx;Tel.:+521-55-56228931

 Received: 16 October 2019; Accepted: 31 December 2019; Published: 4 January 2020

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**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 sugges<sup>t</sup> that ZIKV C6/36 EVs may contribute to the pathogenesis of ZIKV infection in human hosts.

**Keywords:** extracellular vesicles; Zika virus; cellular communication; C6/36 cells; human monocytes; endothelial vascular cells
