title: Zika virus cell tropism in the developing human brain and inhibition by azithromycin.
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 microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, 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. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Hanna
authors.initials: H
authors.lastname: Retallack
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Di Lullo
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.|Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106.
authors.forename: Carolina
authors.initials: C
authors.lastname: Arias
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Kristeene A
authors.initials: KA
authors.lastname: Knopp
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Laurie
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sandoval-Espinosa
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Mancia Leon
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, CA 94122.|Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Robert
authors.initials: R
authors.lastname: Krencik
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, CA 94122.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Ullian
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurological Surgery, University of California, San Francisco, CA 94143.
authors.forename: Julien
authors.initials: J
authors.lastname: Spatazza
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Pollen
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Caleigh
authors.initials: C
authors.lastname: Mandel-Brehm
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Nowakowski
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143; kriegsteina@stemcell.ucsf.edu joe@derisilab.ucsf.edu.|Department of Neurology, University of California, San Francisco, CA 94158.
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Kriegstein
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; kriegsteina@stemcell.ucsf.edu joe@derisilab.ucsf.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
mesh_terms: D017963:Azithromycin / Q000494:pharmacology*; D001921:Brain / Q000196:embryology* / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008826:Microbial Sensitivity Tests; D008831:Microcephaly / Q000188:drug therapy / Q000196:embryology / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D056189:Viral Tropism / Q000187:drug effects* / Q000502:physiology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology*; D000071243:Zika Virus Infection / Q000188:drug therapy* / Q000196:embryology / Q000473:pathology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D017963:Azithromycin; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: Zika virus; azithromycin; cortical development; microcephaly