title: Genetic Ablation of AXL Does Not Protect Human Neural Progenitor Cells and Cerebral Organoids from Zika Virus Infection.
abstract: Zika virus (ZIKV) can cross the placental barrier, resulting in infection of the fetal brain and neurological defects including microcephaly. The cellular tropism of ZIKV and the identity of attachment factors used by the virus to gain access to key cell types involved in pathogenesis are under intense investigation. Initial studies suggested that ZIKV preferentially targets neural progenitor cells (NPCs), providing an explanation for the developmental phenotypes observed in some pregnancies. The AXL protein has been nominated as a key attachment factor for ZIKV in several cell types including NPCs. However, here we show that genetic ablation of AXL has no effect on ZIKV entry or ZIKV-mediated cell death in human induced pluripotent stem cell (iPSC)-derived NPCs or cerebral organoids. These findings call into question the utility of AXL inhibitors for preventing birth defects after infection and suggest that further studies of viral attachment factors in NPCs are needed.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wells
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Max R
authors.initials: MR
authors.lastname: Salick
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ole
authors.initials: O
authors.lastname: Wiskow
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ho
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Worringer
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ihry
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Sravya
authors.initials: S
authors.lastname: Kommineni
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Bilada
authors.initials: B
authors.lastname: Bilican
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Klim
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hill
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Liam T
authors.initials: LT
authors.lastname: Kane
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. Electronic address: ajamete.kaykas@novartis.com.
authors.forename: Ajamete
authors.initials: A
authors.lastname: Kaykas
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: eggan@mcb.harvard.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D016923:Cell Death; D054022:Cerebrum / Q000473:pathology*; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006801:Humans; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D000066829:Neuroprotection; D009940:Organoids / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000071243:Zika Virus Infection / Q000473:pathology / Q000517:prevention & control*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; CRISPR/CAS9; TAM receptors; TYRO3; Zika virus; cerebral organoids; induced pluripotent stem cells; microcephaly; neural progenitor cells