zika virus and microcephaly
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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
Development of the Human Brain
• Cerebral cortex neurons generated during fetal development (GW8 – GW29)
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
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
• 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
Microcephaly Genes Affect Radial Glia Cell Division
Thornton and Woods, Trends in Genetics 2009, Cell Press
Can Viruses Cause Microcephaly?
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
Does Zika Virus Cause Microcephaly? – What do we Know?
Associated Press/Felipe Dana
Percio Campos, EPA Associated Press/Felipe Dana
Associated Press/Felipe Dana
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
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
Ocular Defects Associated with Congenital Zika Virus Infection
Paramacular chorioretinal atrophy
De Paula Freitas JAMA Ophthalmology 2016
Optic disc hypoplasia
What Cells Does Zika Target During Development?
• We can model aspects of human neurogenesis in vitro
VZ
CP
Zika Virus Likely Infects Neural Progenitors
Tang et al. Cell Stem Cell 2016
Immature neurons exhibited lower levels of infection
Zika Virus Likely Infects Neural Progenitorsand Induces Cell Death
Tang et al. Cell Stem Cell 2016
Infected progenitor cells release infectious viral particles
Infection Reduces the Size of Cerebral Organoid Models
Garcez et al., 2016, PeerJ Preprints
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
Flavivirus Entry Receptors
Perera-Lecoin et al., 2014, MDPI
Several Proteins Promote Zika Virus Entry
Hamel et al, 2015 , J. Virology; Meertens et al., 2012, Cell Host and Microbe
AXLTYRO3
HAVCR1(TIM1)
Virus
Analyzing Gene Expression in Single Cells
Virus
Cellular Resolution “Map” of Gene ExpressionHighlights Vulnerable Cell Populations
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
AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
AXL-Expressing Cells in the Fetal Brain
Tom Nowakowski, unpublished
AXL is expressed in the retinal stem cells.
CMZ
Tom Nowakowski, unpublished
Does in vitro System Recapitulate AXL Expression?
Does in vitro System Recapitulate AXL Expression?
Liz Di Lullo, unpublished
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
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?
Tom Nowakowski Elizabeth Di Lullo Hanna Retallack
Joe DeRisi LabArnold Kriegstein Lab
Jeremy Reiter Lab
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