​Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy

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Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy

Qiming LiangcorrespondencePress enter key for correspondence informationemailPress enter key to Email the author, Zhifei Luo, Jianxiong Zeng, Weiqiang Chen, Suan-Sin Foo, Shin-Ae Lee, Jianning Ge, Su Wang, Steven A. Goldman, Berislav V. Zlokovic, Zhen ZhaocorrespondencePress enter key for correspondence informationemailPress enter key to Email the author, Jae U. Jung8,correspondencePress enter key for correspondence informationemailPress enter key to Email the author
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Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/j.stem.2016.07.019
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Introduction
Zika virus (ZIKV), a reemerging arthropod-bone flavivirus, was initially isolated from Rhesus macaque in Uganda as early as 1947, while the first human infection was reported in 1954 (Dick, 1952, Dick et al., 1952, Simpson, 1964). Although sexually transmitted cases have been recently documented, ZIKV is most commonly transmitted through the bites of infected Aedes mosquitoes (Musso et al., 2015, Venturi et al., 2016). Individuals infected by ZIKV typically develop a mild or unapparent dengue-like disease (Duffy et al., 2009). However, mounting evidence has linked ZIKV infection to neurological defects in newborns (De Carvalho et al., 2016). Furthermore, ZIKV was detected in the amniotic fluids of pregnant women as well as in the brain tissues of microcephalic fetuses, suggesting that ZIKV can potentially cross the placental barrier to infect fetuses (Calvet et al., 2016, Mlakar et al., 2016). In addition, an increased rate of Guillain-Barr? syndrome was noted following the ZIKV outbreak in French Polynesia from 2013 to 2014 (Cauchemez et al., 2016). The World Health Organization declared a Public Health Emergency of International Concern (Heymann et al., 2016), and the Centers for Disease Control and Prevention confirmed that ZIKV causes microcephaly and other birth defects. Although ZIKV infection impairs the growth of neurospheres and brain organoids derived from iPSCs (Garcez et al., 2016, Qian et al., 2016), the molecular mechanism by which ZIKV infection induces fetal microcephaly remains elusive. In particular, dengue virus (DENV), a closely related member of the flaviviridae family, has not been linked to either microcephaly or defects in neurogenesis (Garcez et al., 2016), suggesting that ZIKV?s neuropathology might be causally linked to those differences in its sequence from dengue.
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http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30214-4

 

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[h=1]2 Zika proteins responsible for microcephaly identified[/h] [h=2]It?s the first study to examine Zika infection in human neural stem cells from second-trimester fetuses, USC researchers say[/h]

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BY Zen Vuong
AUGUST 11, 2016

Transmission electron microscope image of negative-stained, Fortaleza-strain Zika virus (red), isolated from a microcephaly case in Brazil. (Microscopy/National Institute of Allergy and Infectious Diseases, National Institutes of Health)
[FONT=&quot]USC researchers have tracked down two Zika proteins potentially responsible for thousands of microcephaly cases in Brazil and elsewhere ? taking one small step toward preventing Zika-infected mothers from birthing babies with abnormally small heads.[/FONT]
[FONT=&quot]The Zika virus contains 10 proteins, but only NS4A and NS4B matter when it comes to microcephaly, according to a USC-led study published in the journal Cell Stem Cell on Aug. 11. These miscreant proteins, researchers discovered, have two shared life goals: to handicap fetal brain formation and to mobilize their malevolent forces.[/FONT]
[FONT=&quot]Researchers said they are the first to examine three strains of Zika in second trimester human fetal neural stem cells. Previous studies created tiny neural stem cell organoids from adult origin.[/FONT]
[FONT=&quot]The USC-led study, a collaborative effort between the virology and neurobiology disciplines, is also the first to examine Zika virus on the molecular level, said Jae Jung, senior corresponding author and distinguished professor and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC.[/FONT]
[FONT=&quot]?We now know the molecular pathway, so we made the first big step toward target therapy for Zika-induced microcephaly,? Jung said. ?Years from now, one shot or a series of shots could target the proteins NS4A and NS4B or their collaborators.?
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http://news.usc.edu/105296/2-zika-proteins-responsible-for-microcephaly-identified/[/FONT]