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Zika Virus in the Human Placenta and Developing Brain: Cell Tropism and Drug Inhibition

Hanna Retallack, Elizabeth Di Lullo, Carolina Arias, Kristeene A. Knopp, Carmen Sandoval-Espinosa, Matthew T. Laurie, Yan Zhou, Matthew Gormley, Walter R. Mancia Leon, Robert Krencik, Erik M. Ullian, Julien Spatazza, Alex A. Pollen, Katherine Ona, Tomasz J. Nowakowski, Joseph L. DeRisi, Susan J. Fisher, Arnold R. Kriegstein
doi: https://doi.org/10.1101/058883
Hanna Retallack
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
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Elizabeth Di Lullo
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Carolina Arias
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
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Kristeene A. Knopp
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
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Carmen Sandoval-Espinosa
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Matthew T. Laurie
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
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Yan Zhou
4Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
5Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
6Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA
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Matthew Gormley
4Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
5Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
6Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA
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Walter R. Mancia Leon
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Robert Krencik
7Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94122, USA
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Erik M. Ullian
7Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94122, USA
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Julien Spatazza
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
8Department of Neurological Surgery, University of California-San Francisco, San Francisco, California 94143, USA
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Alex A. Pollen
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Katherine Ona
4Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
5Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
6Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA
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Tomasz J. Nowakowski
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
3Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
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Joseph L. DeRisi
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
9Howard Hughes Medical Institute, Chevy Chase, MD, USA.
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Susan J. Fisher
4Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
5Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA
6Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA
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Arnold R. Kriegstein
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA
2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
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Abstract

The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including placental damage and microcephaly. However, the placenta’s role in viral transmission and the mechanisms of microcephaly have not been addressed in primary human tissues. Moreover, there is an urgent need for drugs that can prevent developmental defects following infection. Here, we identify the placental and brain cell populations most susceptible to ZIKV infection, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by inhibiting viral proliferation. In the early gestation placenta, the virus readily infected trophoblast subpopulations that are in direct contact with maternal blood and uterine cells, suggesting routes of ZIKV transmission to the embryo and fetus. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate and brain abnormalities caused by third trimester infection. Blocking a putative viral entry receptor, AXL, which is highly enriched in the infected placenta and brain cell types, reduced ZIKV infection of astrocytes in vitro. In a glial cell line, the macrolide antibiotic, azithromycin, inhibited viral proliferation and viral-induced cytopathic effects at clinically relevant concentrations. Our characterization of infection in primary human tissues clarifies the pathogenesis of congenital ZIKV infection and provides critical context for interpreting results from model systems. Further work on azithromycin and related compounds may yield additional therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.

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Posted June 15, 2016.
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Zika Virus in the Human Placenta and Developing Brain: Cell Tropism and Drug Inhibition
Hanna Retallack, Elizabeth Di Lullo, Carolina Arias, Kristeene A. Knopp, Carmen Sandoval-Espinosa, Matthew T. Laurie, Yan Zhou, Matthew Gormley, Walter R. Mancia Leon, Robert Krencik, Erik M. Ullian, Julien Spatazza, Alex A. Pollen, Katherine Ona, Tomasz J. Nowakowski, Joseph L. DeRisi, Susan J. Fisher, Arnold R. Kriegstein
bioRxiv 058883; doi: https://doi.org/10.1101/058883
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Zika Virus in the Human Placenta and Developing Brain: Cell Tropism and Drug Inhibition
Hanna Retallack, Elizabeth Di Lullo, Carolina Arias, Kristeene A. Knopp, Carmen Sandoval-Espinosa, Matthew T. Laurie, Yan Zhou, Matthew Gormley, Walter R. Mancia Leon, Robert Krencik, Erik M. Ullian, Julien Spatazza, Alex A. Pollen, Katherine Ona, Tomasz J. Nowakowski, Joseph L. DeRisi, Susan J. Fisher, Arnold R. Kriegstein
bioRxiv 058883; doi: https://doi.org/10.1101/058883

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