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Unraveling the Zika Virus

April 27, 2016

Zika Virus

Background to a Growing Menace

Evidence is mounting that the Zika virus is even more dangerous than originally thought. Brazilian neuroscientists now say that up to 20% of babies born to mothers who contract the Zika virus during pregnancy could suffer from serious neurological conditions. 1

In other findings issued in The New England Journal of Medicine, researchers report that the "ZIKV infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS [central nervous system] injury." 2

These issues extend beyond Zika as the suspected culprit in an alarming rise of microcephaly among Brazilian newborns, characterized by their abnormally small heads and malformed brains. Guillain-Barré syndrome, which leads to muscle weakness and sometimes even paralysis across the general population, is also associated with the virus. 3

Global Health Threat

This all comes as particularly bad news to the more than 64 countries now reporting the presence of the Zika virus.  Health officials worry that Zika is rapidly becoming a global pandemic. There is reason for concern. Transmitted by mosquitos and the biofluids of infected humans, Zika has already infected millions of people and could spread to as many as 2.2 billion people around the world. 4 With no treatment or vaccine currently available, and up to 30% of newborns potentially exposed in affected regions of the world, the Director-General of the World Health Organization recently declared Zika as a Public Health Emergency of International Concern. 5

How did this all happen so quickly? The short answer is it did not. Doctors first discovered the virus in Uganda in 1947. However, they believed that Zika caused only mild symptoms. Most people were over the virus in a week or so. Many more never knew even they had it. Researchers now believe the virus was misdiagnosed as Dengue Fever, a related virus, so it likely went unnoticed and under-reported for decades. Whatever the reason, scientific literature on the subject is so sparse that when Zika first appeared in Brazil in 2015, doctors had no research to fall back on and initially called it "the mystery disease." 6

PerkinElmer Helps Unmask Zika's Dangers to Human "Mini-brains"

In many respects, Zika still is a mystery. While a number of pharmaceutical companies are feverishly working to develop a Zika vaccine, one team of Brazilian researchers under the direction of Dr. Stevens Rehen, Professor of the Institute of Biomedical Sciences at the Federal University of Rio de Janeiro and Head of Research at D'Or Institute for Research and Education (IDOR), has a different goal. His team is using "human induced pluripotent stem (iPS) cells cultured as neural stem cells (NSC), neurospheres, and brain organoids to explore the consequences of ZIKV infection during neurogenesis and growth with 3D culture models." In other words, they created what they call "mini-brains" to simulate the brain function of fetuses at different stages of development. They then infected these mini-brains with Zika and were astounded by the results.

In conducting the final phases of their tests involving immunostaining, apoptosis assays, and Ethidium homodimer labeling to quantify cell death rates, Dr. Rehen's research team relied on PerkinElmer's cell::explorer® platform equipped with the Operetta® High-Content Imaging System and the JANUS® automated liquid handling workstation. The JANUS workstation was able to automate and accelerate sample preparation. The Operetta system, driven by Harmony High Content Imaging and Analysis software, provided the research biologists with digital phase contrast images of cells at 20x magnification. The Harmony software utilized the digital phase contrast images to provide unbiased quantitative data and analysis of cellular morphology for more accurate differentiation of cell phenotypes exposed to the Zika virus during the first months of human brain development.

"What we observed is that the Zika virus is able to kill cells, is able to affect the growth of cells", Dr. Rehen told the BBC. He added that the particular strain of the Zika virus in Brazil is especially dangerous. 7

Dr. Patricia Garcez, a colleague of Rehen and first author of the work published in Science, says the team was shocked to discover the speed and extent of damage caused to the cerebral cortex of the brain by the virus as seen through the Operetta imaging system. "The effect of the Zika virus was very impressive", she told the BBC. "We were all astonished by the fast effect. We saw cell death in three days, a massive cell death. In six days, the neurospheres were completely gone." 8

"Our results demonstrate that ZIKV induces cell death in human iPS-derived neural stem cells, disrupts the formation of neurospheres, and reduces the growth of organoids," the Rehen team reports. In short, "ZIKV infection in models that mimic the first trimester of brain development may result in severe damage." 9

"There is something in the Zika virus that makes it more prone to kill neural cells during development," Dr. Rehen says. "Now we need to search and understand what makes that virus more aggressive to the brain under development during different stages of fetal development."

PerkinElmer instruments are for research use only. Not for use in diagnostic procedures.

References

  1. Wayne Davies, "Zika Virus: Risk Factor Higher Than First Thought, Says Doctors", BBC, May 2, 2016.
  2. Patrícia Brasil, et. al., "Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report", New England Journal of Medicine, March 4, 2016.
  3. Catherine Saint Louis, "Study of Zika Outbreak Estimates 1 in 100 Risk of Micocephaly", The New York Times, March 16, 2016.
  4. Davies, op. cit
  5. World Heath Organization, "WHO Director-General Summarizes The Outcome Of The Emergency Committee Regarding Clusters Of Microcephaly And Guillain-Barré Syndrome", Press Release, February 1, 2016.
  6. Donald G. McNeil, Jr., Simon Romero, and Sabrina Tavernise, "How a Medical Mystery In Brazil Led Doctors to Zika", The New York Times, February 6, 2016.
  7. Davies, op. cit
  8. Ibid.
  9. Patricia P. Garcez, et. al., "Zika Virus Impairs Growth In Human Neurospheres And Brain Organoids", Science, April 10, 2016.

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