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Everything You Need To Know About Zika Virus In 148 Seconds

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What else do you know about the Zika virus? Now with audio you can hear! Follow all your BuzzFeed favorites in one app! Get the BuzzFeed Video app here: http://video.bzfd.it/jVwh/0sP9ew5bcr Check out more awesome BuzzFeedBlue videos!

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The Zika Virus (ZIKV) is part of the flavivirus genus and is the first single-stranded RNA virus to cause congenital birth defects (Mlakar et al., 2016). Specifically, ZIKV maternal infection leads to microcephaly in newborns, but otherwise results in no other organ damage (Mlakar et al., 2016). In addition, mouse models have confirmed this correlation as well as full recovery of viral DNA from human fetal brains (Zhang et al., 2016). Despite substantial proof of causal relationship between maternal ZIKV infection and newborn microcephaly, the molecular mechanism of Zika infection has yet to be fully elucidated. Thus far, scientists have shown that microcephaly in the newborn is caused by cell death in embryonic cortical neural progenitor cells (NPCs) as a result of ZIKV infection in utero (Tang et al., 2016).

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).

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The researchers obtained three human placentas and isolated the three primary placental cells: fibroblast cells, Hofbauer cells (HBC), and cytorophoblast cells. Each cell culture was infected with three different strains of ZIKV: ZIKVcam (strain obtained from Cambodia in 2010), ZIKVMEX (from America in 2016) and ZIKV mr766 (from Uganda in 1947). As well, vero cells, kidney cells from monkeys that are most susceptible to the infections, were used as a positive control.

Then, the researchers used PCR to determine the amount of viral RNA expression in each cell culture. The results are shown in Figure A. Out of the 3 cells, fibroblast cells had the highest percentage of infection and was very similar to the percentage of vero cells. HBCs also had a high percentage of infection, while no cytotrophoblasts were infected.

To check for viral growth, viral RNA was compared relative to the GAPDH (a protein coding gene) every few hours. Plaque assays were done using the supernatant from the PCR experiments to check for viral titre in each cell culture. The results are shown in Figure B. Fibroblast cells had the fastest viral growth, similar to vero cells. HBCs also had significant viral growth. There was no viral growth in cytotrophoblasts and viral tire remained consistent through time.

Figure C shows immunofluorescent staining that was used to visualize ZIKV infection in villious explant tissues. DAPI (in blue) stained for surrounding cell nuclei. J2 (in red) detects viral double stranded RNA and viral non-structural protein. The green stain marked CD163 macrophage cell marker on HBCs. The white arrows are pointing at infected HBC cells, in which the red and green stains are co-localized. This shows that in villous tissue, HBCs are susceptible to ZIKV infection.

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Previous research shows that in order for the infection to spread, the maternal-fetal barrier needs to be infringed (Klase et al., 2016). This is made extremely difficult by the syncytiotrophoblasts which seals all the cells together, preventing large molecules and pathogens from going through it (Klase et al., 2016). There are many different general explanations as to how the virus could potentially cross the maternal fetal barrier, and they may occur actively or passively (Delorme-Axford, Sadovsky, Coyne, 2014). Active transmission of the a virus exploits the existing mechanisms that provide the fetus with nutrients while passive transmission includes tensions that result in the destruction of the syncytium and subsequent infection of the placental cells (Jurado et al., 2016). The results show that infection is successful in two (Fibroblasts, HofBauer cells)  of the three primary placental cells, and this provides evidence for the latter explanation for crossing the maternal-fetal barrier (Jurado et al., 2016). The absence of infection on the cytotrophoblast cells and more research here can contribute a better understanding of the primary mechanism that the ZIKA virus employs.

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)

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In this paper, the authors showed high ZIKV permissiveness in placental-fibroblasts. Fibroblasts have been demonstrated to be ZIKV permissive by other authors, however, Jurado et al. fail to address the implications of such high ZIKV infection in their fibroblasts samples.

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.

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This study uses isolated cell cultures. However, cells act differently in isolated cultures compared to in vivo models. Therefore, in vivo cells may vary in their permissiveness to the ZIKV. For example, high infection of fibroblasts is most likely due to fibroblasts having higher proliferation in isolated cultures (Jurado et al., 2016). As well, cytokine such as type III interferons excreted by surrounding cells may lead to lessened infection susceptibility (Bayer et al., 2016). As a future direction, the authors should study ZIKV infection of fibroblasts and HBCs in in vivo models.

In addition, the authors suggest that previous infection by the DENV may exacerbate ZIKV permissiveness in placental cells (Jurado et al., 2016). This has been shown by Castanha et al. (2017). In this study, the authors showed that anti-flavivirus antibodies are cross reactive and enhance the infection of another virus through antibody-dependent enhancement (ADE). This group of scientists only conducted their studies in maternal serum samples and human cell cultures. Therefore, Jurado et al., (2016) should investigate the role of DENV antibodies in the ZIKV infection of placenta-specific macrophages in vivo as well as in vitro. One group of cells will express DENV antibodies while the control group will not. Demonstrating this phenomenon would improve the way both ZIKV and DENV infections addressed in communities living in the endemic regions of both viruses.

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).

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https://docs.google.com/document/d/1JuoxQa0ZfnvUEgaCFh9UTCPzWwnY3yXkvgfSnxWtHLc/edit?usp=sharing