The authors could have improved in the transparency of their cell samples, although they showed that macrophages indeed perpetrated ZIKV infection in placental-villi, they did not mention the proportion of infected cells and the number of cells infected. They were also unclear about the number of cells obtained from each of the placenta. Therefore in order to be sure that these results are statistically significant, the study should be replicated with a larger sample size. Lastly, although the results were significant, they did not disclose the standard deviation of their statistical analyses. 

 Along demonstrating background immunity as a potential factor for increased ZIKV infection, the authors should compare the proteomics and mRNA transcriptomics of infected macrophages and control cells. This study has been conducted by Garcez et al. (2016) on human neurospheres to understand the molecular consequences of ZIKV infection in induced pluripotent stem cells (iPSCs). Understanding the mRNA expression as a result of ZIKV infection in HofBauer cells would perhaps contribute to finding potential drug targets to minimize the damage of ZIKV infection in pregnant women (Garcez et al., 2016). 

Additionally, the close relation between the onset of microcephaly and the Dengue virus is also important as the ZIKV and DENV are from the same flavivirus family (Jurado et al., 2016). This is possible evidence to show that  previously existing antibodies from a dengue virus infection can facilitate the transcytosis of the ZIKV across the maternal fetal barrier (Jurado et al., 2016). However, more research is required in  this area in order to prove any causative links. If true, then treating the dengue virus can potentially be a good start to reducing the rates of ZIKV infections in certain regions (Jurado et al., 2016). 

In conclusion, the ZIKV crosses the maternal fetal barrier by intruding the syncytiotrophoblast and infecting the primary placental cells. The infection susceptibility of each of the cells to the virus is different, as outlined above.

Figure: Inside the Placenta  (Delorme-Axford et al., 2014)

The ZIKV is endemic to tropical areas and has been subject to outbreaks in the past in both Uganda, and more recently in Brazil (Aldo et al., 2016). The recent outbreak in Brazil has been the largest outbreak thus far and has caused the most damage throughout communities (Aldo et al., 2016). If unaddressed, the ZIKV epidemic will have profound worldwide consequences due to high migration rates (Petersen et al., 2016). Further, the ZIKV epidemic will quickly become a public health burden (Petersen et al., 2016) and may significantly impact the population sizes of countries hosting the Aedes aegypti mosquito, vector of the ZIKV (Zhang et al., 2016). 

Although the cells specifically infected and impacted by ZIKV in the embryo have been discovered, the means of embryonic infection via the mother has not been fully enlightened. As such, a study led by Jurado et al. (2016) aimed to discover permissive cells leading to embryonic ZIKV infection. The authors decided to investigate the placenta as it is the only site of contact between the mother and the fetus (Jurado et al., 2016). Specifically, the authors acknowledged the point of contact at the placental villi and therefore carried their study in this scope. The placental villi are composed of the syncytiotrophoblasts, cytotrophoblasts, placenta-specific macrophages and fibroblasts. Previous data suggests that syncytiotrophoblasts, cells responsible from separating maternal and fetal blood, were resistant to ZIKV infection due to their expression and secretion of type III interferons (Bayer et al., 2016). The authors of this study also suggest that other cells may have decreased ZIKV permissiveness depending on their respective responsiveness to type III interferons (Bayer et al., 2016). Further, placenta-specific macrophages, otherwise known as Hofbauer cells, had been shown to be permissive to the Dengue virus (DENV) which is also endemic to tropical areas (Jurado et al., 2016). As such, the authors hypothesized that Hofbauer cells were also permissive to the ZIKV, leading to fetal infection and microcephaly (Jurado et al., 2016). To test for this hypothesis, the authors sampled cells from villi taken from three placentas. They used various staining techniques to localize specific cell types as well as the ZIKV, co-localization demonstrated infection of the specific cell type.    

To fully understand the scope of research of Jurado et al. (2016), the architecture of the placenta villi must be acknowledged. The villi are the small protrusions of the placental and contain syncytiotrophoblasts which separate maternal and fetal blood (Bayer at al., 2016). The syncytiotrophoblasts can be considered as miniature organs in which lie other cell types such as the cytotrophoblasts forming the endothelium of the syncytiotrophoblasts (Bayer et al., 2016). Fibroblasts, already known to be permissive to the ZIKV (El Ghouzzi et al., 2016), sit between the villous tissue and trophoblasts and participate in the maintenance of the placenta (Bayer et al., 2016).  

Figure: The syncytiotrophoblast (Quicke et al., 2016).