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Zika Virus and Microcephaly

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3/14/16

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 zoneGenerate neurons that migrate to the cortical plateLateralventricleVZCP

Microcephaly is a Rare Neurodevelopmental DisorderCenters for Disease Control and PreventionU.S. Department of Health & Human Services 2-12 cases per 10,000 live births in the US3 standard deviations below average2 standard deviations below average

4

Intellectual Disability

Developmental Delay

Motor Skills Defects

Vision Problems

Hearing LossSymptoms Associated with MicrocephalyCenters for Disease Control and PreventionU.S. Department of Health & Human Services

Microcephaly Genes Affect Radial Glia Cell DivisionThornton 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.SaundersVentricular calcifications (arrows), pachygyria and lissencephaly, thinning of cortex, and hydrocephalous

Does Zika Virus Cause Microcephaly? What do we Know?

Associated Press/Felipe DanaPercio Campos, EPAAssociated Press/Felipe DanaAssociated Press/Felipe Dana

Study of 42 Pregnant Women With Zika Virus

Enrolled symptomatic pregnant women, tested for virus using PCRBrasil et al NEJM 2016

Fetal abnormalities in 12/42 vs. 0/16 in control groupDeath (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 SocietyCalcifications (arrows)Smooth brain (arrowheads)

Flavivirus particles in brainZika virus genome detected

Ocular Defects Associated with Congenital Zika Virus InfectionParamacular chorioretinal atrophy

De Paula Freitas JAMA Ophthalmology 2016Optic disc hypoplasia

What Cells Does Zika Target During Development?

We can model aspects of human neurogenesis in vitro VZCP

Zika Virus Likely Infects Neural ProgenitorsTang 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 2016Infected progenitor cells release infectious viral particles

Infection Reduces the Size of Cerebral Organoid ModelsGarcez et al., 2016, PeerJ Preprints

Possible Routes for ZIKV Neuroinvasiveness Why does virus selectively target neural stem cells?

Associated Press/Felipe DanaPercio Campos, EPAAssociated Press/Felipe DanaAssociated 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

AXLTYRO3HAVCR1(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. VirologyAXL 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.

CMZTom Nowakowski, unpublished

Does in vitro System Recapitulate AXL Expression?

Does in vitro System Recapitulate AXL Expression?

Liz Di Lullo, unpublished

ConclusionStrong 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 QuestionsWhat 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 NowakowskiElizabeth Di LulloHanna RetallackJoe DeRisi LabArnold Kriegstein LabJeremy Reiter Lab