**1. Introduction**

Zika fever is an important *Arbovirus*-caused disease that has surfaced in numerous countries in Asia, Africa and America [1]. The etiological agen<sup>t</sup> of this disease, Zika virus (ZIKV), was initially isolated in 1947 from the blood of sentinel *Rhesus* monkeys during a study on yellow fever transmission in the Zika forest of Uganda, which gave rise to its name [2,3]. Transmission of the ZIKV is primarily

through bites of infected *Aedes* mosquitos, with the most common vectors being *Aedes aegypti* and *Aedes albopictus,* but it can also happen by vertical transmission [4,5]. As a result of vertical transmission, there were alarming cases of Congenital Zika Syndrome, as the virus could cause damage to the placenta, infect placental cells and reach the fetus [6]. A ZIKV particle has a diameter of 25–30 nm and is a member of the *Flaviviridae* family that shares many similarities with other more widely known related viruses such as dengue, West Nile, Japanese encephalitis and yellow fever [4,7]. It has a single-stranded RNA genome with a positive polarity of 11 Kb and encodes a polyprotein precursor that is processed into the structural proteins such as capsid (C), pre-membrane (prM) and envelope (E) along with seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [8,9].

Mast cells are resident immunological cells found abundantly in tissues such as skin, endometrium and placenta that have prominent roles in immunologic reactions [10–13]. Their presence and prevalence in these tissues, along with their proximity to blood vessels, predispose these cells to be among the first immune cells that can be infected by ZIKV after a mosquito bite penetrates the skin. As some of the most frequent symptoms of zika are rash and pruritus, which are relieved by the administration of antiallergic drugs (anti-histamines), this has led us to believe that mast cells can play a role, although not ye<sup>t</sup> elucidated, in the pathogenesis of the disease [14–16]. We hypothesize that it may be one of the cells involved in placental infections, which can directly contribute to vertical transmission.

Although there are no studies in the literature that have investigated the involvement of mast cells in a ZIKV infection to date, mast cells have a proven role in infections by dengue, another *Arbovirus*. Several products originating from mast cells are found at high levels in patients infected by dengue, especially those with plasma leakage [17,18]. While mast cells are permissive to dengue infection, it is most probable that they display a low level of the specific receptors required since the quantity of virus necessary to successfully infect this cell type is always higher than is needed for macrophages and dendritic cells [17,19,20].

HMC-1 cells are a lineage of human mast cells that characteristically express the cytokine receptor c-Kit abundantly and release di fferent cytokines after degranulation stimuli. This cell line possesses the features necessary to serve as an in vitro model for the development of studies on mast cells [21]. HMC-1 has been widely used in studies on degranulation studies, endothelial activation and its interaction with other arboviruses [22–24].

Here, we present our observations on the presence of mast cells in ZIKV-infected human placentae and observed viral replication in these cells. Additionally, we investigated the potential for ZIKV to infect HMC-1 cells as a model system for mast cells and quantified the percentage of infected cells in di fferent MOIs. We further studied the degranulation of these cells after contact/infection with ZIKV by measuring β-hexosaminidase release as well as the expression profiles of TNFα (tumor necrosis factorα), IL-6 (interleukin-6), IL-10 (interleukin-10) and VEGF (vascular endothelial growth factor). As a final point, we evaluated the e ffects of ZIKV infection on the ultrastructure of HMC-1 cells. Together, the findings validate a critical and, to our knowledge, previously unrecognized role for mast cells in the infection and propagation of ZIKV in humans.
