title: Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.
abstract: Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction, which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virus-infected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herrlinger
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Si-Lu
authors.initials: SL
authors.lastname: Yang
authors.affiliation: University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Miami, FL 33136, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Lai
authors.affiliation: Department of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Moore
authors.affiliation: Department of Infectious Diseases, Department of Population Health and Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Brindley
authors.affiliation: Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA chen2014@uga.edu.
authors.forename: Jian-Fu
authors.identifier: 0000-0002-8869-5913
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000330:Aedes; D000818:Animals; D001812:Blood-Brain Barrier / Q000196:embryology / Q000821:virology; D001921:Brain / Q000098:blood supply* / Q000196:embryology* / Q000821:virology; D020785:Central Nervous System Vascular Malformations / Q000196:embryology / Q000821:virology; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008831:Microcephaly / Q000196:embryology / Q000821:virology*; D018919:Neovascularization, Physiologic; D009421:Nervous System Malformations / Q000196:embryology / Q000821:virology; D058953:Neural Stem Cells / Q000502:physiology / Q000821:virology; D055495:Neurogenesis / Q000502:physiology; D011247:Pregnancy; D014709:Vero Cells; D000071244:Zika Virus / Q000502:physiology; D000071243:Zika Virus Infection / Q000196:embryology*
keywords: Astrogliosis; Blood–brain barrier (BBB); Microcephaly; Microglial activation; ZIKV