zika virus and microcephaly
TRANSCRIPT
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05/03/2023
Zika Virus and Microcephaly
Preparedness for the Zika Virus:A Public Health EmergencyAlex Pollen, Kriegstein LabUniversity of California, San FranciscoMarch 7th 2016
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Development of the Human Brain
• Cerebral cortex neurons generated during fetal development (GW8 – GW29)
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Radial Glia Generate Cortical Neurons
• Radial glia neural stem cells line the ventricular zone• Generate neurons that migrate to the cortical plate
Lateralventricle
VZ
CP
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Microcephaly is a Rare Neurodevelopmental Disorder
Centers for Disease Control and PreventionU.S. Department of Health & Human Services
2-12 cases per 10,000 live births in the US
3 standard deviations below average
2 standard deviations below average
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• Intellectual Disability
• Developmental Delay
• Motor Skills Defects
• Vision Problems
• Hearing Loss
Symptoms Associated with Microcephaly
Centers for Disease Control and PreventionU.S. Department of Health & Human Services
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Microcephaly Genes Affect Radial Glia Cell Division
Thornton and Woods, Trends in Genetics 2009, Cell Press
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Can Viruses Cause Microcephaly?
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Can Viruses Cause Microcephaly?Newborn infant with congenital CMV infection
Swanson Pediatr. Clin. North. Am. 2013, W.B.Saunders
• Ventricular calcifications (arrows), pachygyria and lissencephaly, thinning of cortex, and hydrocephalous
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Does Zika Virus Cause Microcephaly? – What do we Know?
Associated Press/Felipe Dana
Percio Campos, EPA Associated Press/Felipe Dana
Associated Press/Felipe Dana
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Study of 42 Pregnant Women With Zika Virus• Enrolled symptomatic pregnant women, tested for virus using PCR
Brasil et al NEJM 2016
• Fetal abnormalities in 12/42 vs. 0/16 in control group• Death (2), growth defects/microcephaly (5), ventricular calcifications
(7), abnormal amniotic fluid or arterial flow
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Zika Virus Detected in Microcephalic Fetal Brain
Mlakar et al NEJM 2016, Massachusetts Medical Society
• Calcifications (arrows)• Smooth brain (arrowheads)
• Flavivirus particles in brain• Zika virus genome detected
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Ocular Defects Associated with Congenital Zika Virus Infection
Paramacular chorioretinal atrophy
De Paula Freitas JAMA Ophthalmology 2016
Optic disc hypoplasia
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What Cells Does Zika Target During Development?
• We can model aspects of human neurogenesis in vitro
VZ
CP
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Zika Virus Likely Infects Neural Progenitors
Tang et al. Cell Stem Cell 2016
Immature neurons exhibited lower levels of infection
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Zika Virus Likely Infects Neural Progenitorsand Induces Cell Death
Tang et al. Cell Stem Cell 2016
Infected progenitor cells release infectious viral particles
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Infection Reduces the Size of Cerebral Organoid Models
Garcez et al., 2016, PeerJ Preprints
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Possible Routes for ZIKV Neuroinvasiveness – Why does virus selectively target neural stem cells?
Associated Press/Felipe Dana
Percio Campos, EPA Associated Press/Felipe Dana
Associated Press/Felipe Dana
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Flavivirus Entry Receptors
Perera-Lecoin et al., 2014, MDPI
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Several Proteins Promote Zika Virus Entry
Hamel et al, 2015 , J. Virology; Meertens et al., 2012, Cell Host and Microbe
AXLTYRO3
HAVCR1(TIM1)
Virus
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Analyzing Gene Expression in Single Cells
Virus
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Cellular Resolution “Map” of Gene ExpressionHighlights Vulnerable Cell Populations
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Cellular Resolution “Map” of Gene ExpressionHighlights Vulnerable Cell Populations
Hamel et al, 2015 , J. Virology
AXL is necessary and sufficient for Zika virus entry in skin cells
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AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
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AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
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AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
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AXL is expressed in the retinal stem cells.
CMZ
Tom Nowakowski, unpublished
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Does in vitro System Recapitulate AXL Expression?
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Does in vitro System Recapitulate AXL Expression?
Liz Di Lullo, unpublished
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Conclusion• Strong published evidence that Zika virus causes
microcephaly and other abnormalities
• Zika virus may target radial glia neural stem cells
• AXL is a strong candidate entry receptor in brain and eye, based on results in skin and CNS expression pattern
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Outstanding Questions• What are consequences of virus in larger cohort,
including asymptomatic pregnant women?
• Why is Zika virus associated with microcephaly, when Dengue virus is not?
• Is this new strain of Zika virus different from previous strains?
• How does virus cross placenta and blood-brain barrier?
• Is AXL necessary for viral entry and infectivity in neural stem cells?
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Tom Nowakowski Elizabeth Di Lullo Hanna Retallack
Joe DeRisi LabArnold Kriegstein Lab
Jeremy Reiter Lab
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