title: Zika Virus Targeting in the Developing Brain.
abstract: Zika virus (ZIKV), a positive-sense RNA flavivirus, has attracted considerable attention recently for its potential to cause serious neurological problems, including microcephaly, cortical thinning, and blindness during early development. Recent findings suggest that ZIKV infection of the brain can occur not only during very early stages of development, but also in later fetal/early neonatal stages of maturation. Surprisingly, after peripheral inoculation of immunocompetent mice on the day of birth, the first cells targeted throughout the brain were isolated astrocytes. At later stages, more neurons showed ZIKV immunoreactivity, in part potentially due to ZIKV release from infected astrocytes. In all developing mice studied, we detected infection of retinal neurons; in many mice, this was also associated with infection of the lateral geniculate, suprachiasmatic nuclei, and superior colliculus, suggesting a commonality for the virus to infect cells of the visual system. Interestingly, in mature mice lacking a Type 1 interferon response (IFNR-/-), after inoculation of the eye, the initial majority of infected cells in the visual system were glial cells along the optic tract. ZIKV microinjection into the somatosensory cortex on one side of the normal mouse brain resulted in mirror infection restricted to the contralateral somatosensory cortex without any infection of midline brain regions, indicating the virus can move by axonal transport to synaptically coupled brain loci. These data support the view that ZIKV shows considerable complexity in targeting the CNS and may target different cells at different stages of brain development.SIGNIFICANCE STATEMENTZika virus (ZIKV) can cause substantial damage to the developing human brain. Here we examine a developmental mouse model of ZIKV infection in the newborn mouse in which the brain is developmentally similar to a second-trimester human fetus. After peripheral inoculation, the virus entered the CNS in all mice tested and initially targeted astrocytes throughout the brain. Infections of the retina were detected in all mice, and infection of CNS visual system nuclei in the brain was common. We find that ZIKV can be transported axonally, thereby enhancing virus spread within the brain. These data suggest that ZIKV infects multiple cell types within the brain and that astrocyte infection may play a more important role in initial infection than previously appreciated.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520 anthony.vandenpol@yale.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: van den Pol
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Guochao
authors.initials: G
authors.lastname: Mao
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Sara
authors.identifier: 0000-0001-6898-7217
authors.initials: S
authors.lastname: Ornaghi
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: John N
authors.initials: JN
authors.lastname: Davis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000998:Antiviral Agents / Q000627:therapeutic use; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000821:virology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D006801:Humans; D016867:Immunocompromised Host; D007372:Interferons / Q000627:therapeutic use; D001523:Mental Disorders / Q000209:etiology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000209:etiology / Q000821:virology; D009457:Neuroglia / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000473:pathology / Q000821:virology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D000071244:Zika Virus / Q000472:pathogenicity*; D000071243:Zika Virus Infection / Q000150:complications / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000998:Antiviral Agents; D017471:Receptors, Interferon; D007372:Interferons
keywords: astrocyte; behavior dysfunction; development; infection; neurotropic; virus