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Zika virus spreads during brain growth spurts

Scientists from the Florida campus of The Scripps Research Institute (TSRI) are able to pinpoint timing of the most aggressive ZIKA attacks on newborn mouse brains — information that could help treatments.

The study, led by The Scripps Research Institute (TSRI) Associate Professors Hyeryun Choe and Damon Page, was published recently in the journal Nature Scientific Reports.

In the new study, the scientists observed the virus's effects in animal models at two different points: Initially — during early postnatal development, when the brain is growing rapidly, and Secondarily — at weaning, when the brain has largely reached adult size.

"In early postnatal Zika-infected models some brain areas and cell types showed particularly large increases in apoptosis [programmed cell death] that we did not observe in older animals," explained Hyeryun Choe.

The findings expand our current knowledge of cell types most vulnerable to Zika infection.

Not only the earliest form of neuron cells, but post-mitotic neurons which have finished dividing, but still rapidly increase in cell size.

Results are consistent with the idea that rapid brain growth is especially susceptible to damage by Zika infection.

First isolated in rhesus macaque monkeys in Uganda in 1947, Zika is transmitted by mosquito bite. Related to several other human pathogens, including West Nile virus, dengue, Japanese encephalitis virus and yellow fever, the 2015 Zika epidemic in Brazil coincided with a dramatic increase in cases of microcephalic newborns.

"An interesting aspect of the study is the comparison of the two time points. There is neural cell death at both times, but it's much greater when the brain is growing rapidly.

"We can take advantage of this to test potential treatments and to understand whether some genetic backgrounds may confer enhanced susceptibility or resilience to Zika-induced microcephaly."

Damon Page, The Doctoral Program in Chemical and Biological Sciences at The Scripps Research Institute, Jupiter, Florida, USA

The team is continuing to build on this study to better understand and combat the virus.

"Our findings establish a valuable model to investigate the mechanisms that underlie the horrific birth defects associated with Zika infection,"
said TSRI Graduate Student Wen-Chin Huang, the first author of the study.

Zika virus (ZIKV) infection in pregnant women has been established as a cause of microcephaly in newborns. Here we test the hypothesis that neurodevelopmental stages when the brain is undergoing rapid growth are particularly vulnerable to the effects of ZIKV infection. We injected ZIKV intracranially into wild type C57BL/6 mice at two different time points: early postnatal development, when the brain is growing at its maximal rate, and at weaning, when the brain has largely reached adult size. Both time points showed widespread immunoreactivity for ZIKV and cleaved caspase 3 (CC3, a marker of apoptosis) throughout the brain. However, in early postnatal ZIKV injected mice, some brain areas and cell types display particularly large increases in apoptosis that we did not observe in older animals. Corticospinal pyramidal neurons, a cell type implicated in human microcephaly associated with ZIKV infection, are an example of one such cell type. Proliferating cells in the ventricular zone stem cell compartment are also depleted. These findings are consistent with the hypothesis that periods of rapid brain growth are especially susceptible to neurodevelopmental effects of ZIKV infection, and establish a valuable model to investigate mechanisms underlying neurodevelopmental effects of ZIKV infection and explore candidate therapeutics.

In addition to Choe, Page and Huang, other authors of the study, "Zika Virus Infection During the Period Of Maximal Brain Growth Causes Microcephaly and Corticospinal Neuron Apoptosis in Wild Type Mice," include Rachy Abraham and Byoung-Shik Shim of TSRI.

The study was supported by the National Institutes of Health (grant R01 AI110692) and by Ms. Nancy Lurie Marks.

About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine -- work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

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Oct 24, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Mice were injected intracranially with Saline or ZIKV i.e. Zika Virus (MR766) at one week of age.
(D) Images of mouse type anti-Iba1 (GREEN) and mouse type anti-GFAP (RED) brain staining.
(E) Higher magnification of ZIKV wild type mouse brains show results consistent with infection.

Image Credit:
Hyeryun Choe and Damon Page, TSRI


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