August 17

Zika: Has this virus lost its bite?

Do you live in a generally cool, dry place and rarely think about mosquitoes? Was last year’s Zika outbreak of little personal concern? You may not have the option of staying carefree for much longer. The Zika-carrying Aedes aegypti mosquito is already enjoying widespread breeding grounds as temperatures steadily rise across the globe, indicating that Zika could soon spread to regions of the world never predicted in the past.

This time last year, the word “Zika” seemed to pack a harder punch. People were panicked, and with good reason. In February 2016, the World Health Organization (WHO) declared the Zika outbreak a Public Health Emergency of International Concern (PHEIC) as evidence of its link to neurological impairment grew. In May 2016, the WHO definitively concluded that Zika infection during pregnancy could cause developmental abnormalities in the fetus, one of which was microcephaly, or decreased brain size. Zika was also established as a trigger of the autoimmune disorder Guillain-Barré syndrome (GBS). This outbreak came at an especially inopportune time, ahead of the Summer Olympics in Rio De Janeiro, Brazil—the eye of the storm [1].

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Zika wasn’t discovered recently—we’ve known of its existence for decades. It was first isolated from monkeys in Uganda’s Ziika forest in 1947, and the small number of Zika cases reported were limited to Africa and Asia, until the mid- 2000s [2]. Zika was initially considered a virus of minimal consequence, resulting in a fever, rash, and general flu-like symptoms, and was thus somewhat overlooked until more recently when it was linked to congenital birth defects.

Zika hasn’t gone anywhere

Although some of the initial anxiety surrounding the virus has faded, earlier this month Zika was reported in Texas, serving as a reminder that this virus has endured and that, despite the efforts of hundreds of researchers, no vaccine currently exists [3].

In the time since the Zika outbreak was declared a public health emergency, the virus was discovered to be transmitted not only by mosquitoes but through sexual intercourse. Now, mouse models are enabling us to understand the transmission process. Male mice infected with a species-specific Zika virus have shown significant testicular tissue damage, leading to decreased testosterone levels. Zika infection was most prominent in early stage spermatocytes, the cells that give rise to sperm, as well as in Sertoli cells, the support cells of the testis that are essential for normal sperm production and fertility. This study brought attention to the importance of long-term fertility research, that continues well after a patient has cleared the virus from his or her system [4]. Female mice are providing clues as to how efficiently Zika is transmitted from males to females and its capacity to replicate in the vagina. Once a virus infects a cell it can replicate, and by doing so it increases its own likelihood of survival. Initial work has shown that Zika can continue to replicate for at least ten days in the mouse female reproductive tract and that, as hormone levels change throughout a mouse’s estrous cycle, risk of infection changes as well [5].

In November of 2016, the WHO Director-General declared the end of the Zika PHEIC, shifting the focus toward long-term strategies for its management. In other words, Zika wasn’t going anywhere and so lasting policies needed to be implemented with the hope of an eventual vaccine, which leads us to the question: How close are we to developing one? Since the beginning of August dozens of Zika research studies have been published and the race for a vaccine is in full swing.

The quest to cure (or better yet prevent) Zika infection

In order to create a working vaccine, scientists are attempting to understand what it is about this virus that allows it to cause debilitating neurological effects, and are finding that much can be learned from related viruses. Zika holds many similarities to dengue, and so based on the less than optimal dengue vaccine on the market there is concern surrounding the feasibility of a wholly protective Zika vaccine [6]. Nevertheless, making these comparisons is an ongoing strategy for vaccine development and implementation.

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Researchers have observed that response to Zika greatly varies among those infected: Not everyone infected with Zika suffers from GBS or gives birth to a child with microcephaly. Scientists are working to understand this varied susceptibility of individuals by infecting human neural stem cells (hNSCs) with the virus [7]. Recently, one group of researchers tested three strains of hNSCs, one cell strain representing one patient, and discovered that, although all three strains were successfully infected, only two of the three patient strains exhibited reduced cellular differentiation, or progression along the neural cell lineage, a hallmark of microcephaly. The third strain differentiated normally, providing a potential model for individuals who could be infected with Zika yet never experience damaging neurological effects. As variation in gene expression likely underlies this ability to develop normally in the presence of this typically menacing virus, all three cell strains were sequenced to look for differences in gene expression. Cell lines infected with Zika showed increased expression of genes related to immune response and inflammation, but the implications of this variability in neural development is not well understood. Although an ongoing area of research, scientists have not yet been able to pinpoint the genes responsible for reduced neuronal cell differentiation in the presence of Zika.

Dozens of drugs have now been screened in human neural progenitor cells (hNPCs) that have been infected with Zika [8]. A small number of those drugs were found to eliminate the virus after infection and, in human forebrain organoids, reverse the microcephaly phenotype. Organoids, often referred to as “brains in a dish,” have the three dimensional architecture and multiple cell types seen in a developing fetal brain. A couple of the screened drugs were found to block Zika infection in mice, and in those mice who were intentionally infected, the administration of one of the drugs actually suppressed the virus from spreading. Although this work does not directly contribute to the creation of a preventative vaccine, it is still important for understanding how the Zika virus functions and what may destabilize it.

In mice, a synthetically produced protein (named Z2) was discovered to inhibit Zika infection and transmission [9]. This antiviral treatment in mice brings hope to the eventual possibility of preventing transmission between mother and fetus in humans. Mice are also being utilized to model the main mode of human infection: a mosquito bite [10]. Researchers are exposing mosquitoes carrying Zika to mice and then monitoring progression of the virus post-infection. Although this research was just published, this is a promising model of Zika infection that will likely be used in the future for drug and vaccine development.

Using what we already know and looking toward the future

Although various vaccine and drug candidates are in the process of development and testing, the prospect of repurposing drugs already on the market is appealing, as although it would still require clinical trials, it would cut time and cost and more quickly provide a patient with what he or she needs. For example, a FDA-approved drug to treat neurodegenerative disease Alzheimer’s has recently been shown to prevent some of the neuronal cell death that typically results from Zika infection [11]. The drug targets N-methyl-D-aspartate receptors (NMDARs), cell receptors whose overstimulation may be in part responsible for degeneration of the myelin sheath, a fatty substance surrounding the axons of nerve cells essential for nervous system function. Myelin sheath is often also degraded upon Zika infection leading to partial or, in most extreme cases, full paralysis. By blocking NMDAR activity this degradation may decrease.

In addition to ongoing research, postmortem data continues to be collected, and is in agreement with what has already been established: Zika infection affects neural development and can be transmitted from mother to fetus during gestation [12].

As is now hopefully clear, research being done in human cell lines and in mice has yielded encouraging results, but there’s still considerable work to do before a vaccine or drug treatment is brought to market. Although the threat of Zika may have somewhat lapsed out of public consciousness, global warming is allowing for it to spread beyond what would have been imagined in the past. Let’s all hope that the thousands of hours of research and global activism prevail, but in the meantime, find ways to remain engaged and stay informed.

Courtesy of Dexter on Showtime

  1. Heukelbach, J. (2016). Zika virus outbreak in Brazil. J Infect Dev Ctries, 10(2), 116-120.
  2. Dick, GWA. (1952). Zika Virus (I) Isolations and serological specificity. Trans R Soc Trop Med Hyg, 46(5), 509-520.
  3. Shirley, D-AT. (2017). Zika Virus Infection. Pediatr Clin North Am, 64(4), 937-951.
  4. Govero, J. (2016). Zika virus infection damages the testes in mice. Nature, 540(7633), 438-442.
  5. Tang, WW. (2016). A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication. Cell Rep, 17(12), 3091-3098.
  6. Halstead, SB. (2017). Achieving safe, effective, and durable Zika virus vaccines: lessons from dengue. Lancet Infect Dis, 1473-3099(17), 30362-6.
  7. McGrath, EL. (2017). Differential Responses of Human Fetal Brain Neural Stem Cells to Zika Virus Infection. Stem Cell Reports, 8(3), 715-727.
  8. Zhou, T. (2017). High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates That Inhibit Zika Virus Infection in Fetal-Like Organoids and Adult Brain. Cell Stem Cell, 21, 1–10.
  9.  Yu, Y. (2017). A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nature, 8:15672.
  10.  Secundino, NFC. (2017). Zika virus transmission to mouse ear by mosquito bite: a laboratory model that replicates the natural transmission process. Parasites & Vectors, 10(1), 346.
  11.  Costa, VV. (2017). N-Methyl-D-Aspartate (NMDA) receptor blockade prevents neuronal death induced by Zika virus infection. MBio, 8(2).
  12.  Schwartz, DA. (2017). Autopsy and postmortem studies are concordant: Pathology of zika virus infection is neurotropic in fetuses and infants with microcephaly following transplacental transmission. Archives of Pathology and Laboratory Medicine, 141(1), 68–72.

-Samantha H. Jones is a Ph.D. student in the Biomedical Sciences program at UCSD. When not in the lab, you can find her writing, teaching yoga, and spending time outside appreciating the beautiful San Diego weather. She’s working toward a future that involves science journalism and increasing public science literacy through education and conversation.

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