Rescuing Neurons from Zika Virus Infection
Article Aug 25, 2017 | by Adam Tozer PhD
Since the widespread epidemic of 2015, the Aedes mosquito-borne Zika virus has spread to a growing number of countries. It causes mild flu-like symptoms in infected individuals and can cause microcephaly in the unborn foetus.
Zika virus: causes, outbreak, symptoms & pathology, by Osmosis.
Mosquitoes cannot directly infect unborn foetuses, but they can bite and infect pregnant mothers who pass on the infection to the foetus. The virus can also be transmitted through sexual contact and the resulting infection passed onto the foetus. Investigations of Zika virus’ infectivity profile have shown that it crosses the placenta and infects cells destined to become neurons. By killing these cells, it impairs brain development causing microcephaly.
What other cells are vulnerable to the Zika virus?
The Zika virus is a Flavivirus normally cleared from our blood within 7 days. However, it has been shown to reside in tissue for longer periods of time. For example, a study in infected monkeys showed that the Zika virus hides out in neurons and lymph nodes for months after blood tests stopped detecting evidence of the virus.
Read more: Zika hides out in the body for months
In a recent study from Prof. Guo-Li Ming’s lab at the Perelman School of Medicine, University of Pennsylvania, teamed up with Dr. Gabsang Lee’s lab at Johns Hopkins University to investigate the source of painful symptoms associated with Zika virus infection that suggested the peripheral nervous system was compromised by the virus. Their work employed mouse models to explore the progression of the viral infection and the mechanism by which it affected the peripheral neurons, leading to neuronal death. By looking at the level of individual genes the scientists could explore how the Zika Virus changed gene expression in the peripheral neurons gaining insight as to which genes were ‘switched-on’ or ‘off’ by the virus.
Understanding the mechanisms of infection at this level is very powerful in enabling scientists to find therapeutic targets to prevent the destruction caused by the virus. As Guo-Li explains, “We have identified the molecular pathology, which can be used as a target for the identification of therapeutic interventions.”
Developing and repurposing therapies to fight Zika
Right now there is no vaccine to protect against Zika virus infection, although some are in development that have shown promising results in tests in primates. There are also no drugs to treat against the virus on the market. The current CDC advice to treat Zika virus infection is akin to that of the common cold, requiring rest, painkillers and quarantine. Unfortunately, this advice cannot stop the virus causing microcephaly in the developing foetus.
A recent paper, also from Guo-Li’s lab, developed a phenotypic screen to look for small molecules that could prevent Zika virus from infecting developing neuronal cells, akin to those growing in the foetal brain.
Rather than start the drug development process from scratch, they used a high-throughput approach to screen ~6,000 drugs already on the market or in later stages of development against Zika virus infectivity. They found: Emricasan, a drug currently in phase 2 clinical trials for the treatment of liver fibrosis in hepatitis; 10 Cyclin Dependent Kinase inhibitors; and Niclosamide, a drug currently on the market for treating worm infections, all prevented Zika Virus carrying out its destructive action on neuronal precursor cells.
A complimentary study from Shelton Bradrick and Mariano Garcia-Blanco’s groups at The University of Texas looked at several different cell types, such as those derived from genital, placental and neural tissues. They tested 774 FDA-approved compounds and found over 20 of these were effective in preventing Zika virus infectivity.
Using phenotypic screens to look for new tricks with old drugs
Jacob Tesdorpf, Director of High Content and Direct Detection Instrumentation at PerkinElmer explains the power of phenotypic screening and drug repurposing, “Phenotypic screening enables researchers to directly observe the effect of a molecule or compound on a cell or a system, and collect multiple data streams in a single experiment.”
Whatever the assay, whether cells in a dish or model organisms like zebra fish, the ability to test the efficacy of a compound on a disease phenotype is a powerful tool for drug discovery.
Given the cost of drug development is currently estimated to be between $2 billion and $3 billion US and take between 13-15 years, the ability to test libraries of compounds already known to be safe for use in humans in these screens creates a speedier and more economically viable route to therapy development.
Learn more: repurposing drugs to treat disease
The availability of compound libraries to academic labs and the sharing of data in repositories means that re-screening compounds to treat conditions they were not originally intended for is a growing global trend. As Jacob explains, “Our phenotypic screening instruments are in academic labs and institutions worldwide, helping to assist in research towards finding treatments for dementia, cancer and infectious diseases like Zika.”
Indeed, Guo-Li confirms "We are actively looking to find an agent that could be repurposed to prevent or treat Zika virus infection of peripheral neurons.”
Understanding the in-depth molecular pathology of disease and using this knowledge to better design phenotypic screening assays, and combining this with repurposed drug libraries offers a brighter, cheaper future for drug discovery.
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