Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities.

The re-emergence of Zika virus (ZIKV) and its suspected link with various disorders in newborns and adults led the World Health Organization to declare a global health emergency. In response, the stem cell field quickly established platforms for modeling ZIKV exposure using human pluripotent stem cell-derived neural progenitors and brain organoids, fetal tissues, and animal models. These efforts provided significant insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection as well as platforms for drug testing. Here we review the remarkable progress in stem cell-based ZIKV research and discuss current challenges and future opportunities.

[1]  J. Roehrig,et al.  The Murray Valley encephalitis virus prM protein confers acid resistance to virus particles and alters the expression of epitopes within the R2 domain of E glycoprotein , 1992, Virology.

[2]  L. Rodrigues,et al.  Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. , 2016, The Lancet. Infectious diseases.

[3]  Hongda Li,et al.  Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. , 2016, Cell stem cell.

[4]  C. Mengelle,et al.  Zika virus in semen and spermatozoa. , 2016, The Lancet. Infectious diseases.

[5]  Marko Kolenc,et al.  Zika Virus Associated with Microcephaly. , 2016, The New England journal of medicine.

[6]  P. Desprès,et al.  A robust method for the rapid generation of recombinant Zika virus expressing the GFP reporter gene. , 2016, Virology.

[7]  A. Barrett,et al.  Fast-Track Zika Vaccine Development - Is It Possible? , 2016, The New England journal of medicine.

[8]  A. Brass,et al.  The IFITMs Inhibit Zika Virus Replication. , 2016, Cell reports.

[9]  C. Studholme,et al.  Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate , 2016, Nature Medicine.

[10]  T. Rana,et al.  Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. , 2016, Cell stem cell.

[11]  T. Hodge,et al.  Zika Virus Induced Mortality and Microcephaly in Chicken Embryos. , 2016, Stem cells and development.

[12]  Emily M. Lee,et al.  Molecular signatures associated with ZIKV exposure in human cortical neural progenitors , 2016, bioRxiv.

[13]  F. Heinz,et al.  Proteolytic activation of tick-borne encephalitis virus by furin , 1997, Journal of virology.

[14]  L. Zon,et al.  Engineering Hematopoietic Stem Cells: Lessons from Development. , 2016, Cell stem cell.

[15]  Chuan He,et al.  RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation , 2015, Genes & development.

[16]  John H. Morris,et al.  Global landscape of HIV–human protein complexes , 2011, Nature.

[17]  F. Gage,et al.  In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector , 1996, Science.

[18]  S. Goldman,et al.  Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. , 2016, Cell stem cell.

[19]  Nikos Vasilakis,et al.  A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. , 2016, Cell host & microbe.

[20]  A. Pletnev,et al.  A Full-Length Infectious cDNA Clone of Zika Virus from the 2015 Epidemic in Brazil as a Genetic Platform for Studies of Virus-Host Interactions and Vaccine Development , 2016, mBio.

[21]  R. Vance,et al.  STING and the innate immune response to nucleic acids in the cytosol , 2012, Nature Immunology.

[22]  E. J. Field,et al.  Zika virus infection of the central nervous system of mice , 2005, Archiv für die gesamte Virusforschung.

[23]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[24]  David W. Nauen,et al.  Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure , 2016, Cell.

[25]  Alex A. Pollen,et al.  Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells. , 2016, Cell stem cell.

[26]  D. Missé,et al.  Biology of Zika Virus Infection in Human Skin Cells , 2015, Journal of Virology.

[27]  Joshua E. Elias,et al.  Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens , 2016, Nature.

[28]  D. Tortorella,et al.  Rescue of the 1947 Zika Virus Prototype Strain with a Cytomegalovirus Promoter-Driven cDNA Clone , 2016, mSphere.

[29]  S. Harrison,et al.  The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution , 1995, Nature.

[30]  M. Götz,et al.  Developmental cell biology: The cell biology of neurogenesis , 2005, Nature Reviews Molecular Cell Biology.

[31]  Christopher A Walsh,et al.  Genetic causes of microcephaly and lessons for neuronal development , 2013, Wiley interdisciplinary reviews. Developmental biology.

[32]  G. Ming,et al.  Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later. , 2015, Cell stem cell.

[33]  N. Krogan,et al.  Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. , 2016, Immunity.

[34]  J. Vlak,et al.  Noncoding Flavivirus RNA Displays RNA Interference Suppressor Activity in Insect and Mammalian Cells , 2012, Journal of Virology.

[35]  P. Garcez,et al.  Zika virus impairs growth in human neurospheres and brain organoids , 2016, Science.

[36]  Charles M. Rice,et al.  Flaviviridae :T he Viruses and Their Replication , 2007 .

[37]  Ruili Huang,et al.  Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen , 2016, Nature Medicine.

[38]  Ralf Bartenschlager,et al.  Composition and Three-Dimensional Architecture of the Dengue Virus Replication and Assembly Sites , 2009, Cell Host & Microbe.

[39]  Sean P. Palecek,et al.  Human Blood-Brain Barrier Endothelial Cells Derived from Pluripotent Stem Cells , 2012, Nature Biotechnology.

[40]  S. Meloche,et al.  The IKK-related kinases: from innate immunity to oncogenesis , 2008, Cell Research.

[41]  J. Kieft,et al.  Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease , 2016, Science.

[42]  Amadou Alpha Sall,et al.  Zika virus and microcephaly: why is this situation a PHEIC? , 2016, The Lancet.

[43]  J. Brault,et al.  Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex , 2016, EBioMedicine.

[44]  Emmanuel Fournier,et al.  Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study , 2016, The Lancet.

[45]  R. DeBiasi,et al.  Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities , 2016 .

[46]  Madeline A. Lancaster,et al.  Stem Cell Models of Human Brain Development. , 2016, Cell stem cell.

[47]  Cynthia J. Burrows,et al.  Zika Virus Genomic RNA Possesses Conserved G-Quadruplexes Characteristic of the Flaviviridae Family , 2016, ACS infectious diseases.

[48]  S. Rasmussen,et al.  Zika Virus and Birth Defects--Reviewing the Evidence for Causality. , 2016, The New England journal of medicine.

[49]  Peng Jin,et al.  Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. , 2016, Cell stem cell.

[50]  C. Power,et al.  Zika virus inhibits type‐I interferon production and downstream signaling , 2016, EMBO reports.

[51]  Li-Huei Tsai,et al.  Efficient derivation of microglia-like cells from human pluripotent stem cells , 2016, Nature Medicine.

[52]  Hans Clevers,et al.  Modeling Development and Disease with Organoids , 2016, Cell.

[53]  Eric D'Ortenzio,et al.  Evidence of Sexual Transmission of Zika Virus. , 2016, The New England journal of medicine.

[54]  Xuping Xie,et al.  Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus , 2016, Open forum infectious diseases.

[55]  J. Molès,et al.  Zika Virus Strains Potentially Display Different Infectious Profiles in Human Neural Cells , 2016, EBioMedicine.

[56]  M. L. B. Ferreira,et al.  Guillain-Barré syndrome associated with the Zika virus outbreak in Brazil. , 2016, Arquivos de neuro-psiquiatria.

[57]  M. Beltramello,et al.  Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection , 2016, Science.

[58]  A. Kriegstein,et al.  Development and Evolution of the Human Neocortex , 2011, Cell.

[59]  Robert E. Schmidt,et al.  A complement–microglial axis drives synapse loss during virus-induced memory impairment , 2016, Nature.

[60]  A. Brass,et al.  Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. , 2016, Cell reports.

[61]  J. Qian,et al.  DNA methylation presents distinct binding sites for human transcription factors , 2013, eLife.

[62]  J. Izopet,et al.  ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy , 2016, Scientific Reports.

[63]  Su-Chun Zhang,et al.  Neural Subtype Specification from Human Pluripotent Stem Cells. , 2016, Cell stem cell.

[64]  A. Barrett,et al.  An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors. , 2016, Cell host & microbe.

[65]  S. Halstead,et al.  Antibody-enhanced dengue virus infection in primate leukocytes , 1977, Nature.

[66]  E. Dueber,et al.  Recent insights into the complexity of Tank‐binding kinase 1 signaling networks: The emerging role of cellular localization in the activation and substrate specificity of TBK1 , 2013, FEBS letters.

[67]  D. Geschwind,et al.  Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture , 2015, Nature Methods.

[68]  M. Eiraku,et al.  Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell–derived neocortex , 2013, Proceedings of the National Academy of Sciences.

[69]  Myrielle Dupont-Rouzeyrol,et al.  Detection of Zika Virus in Urine , 2015, Emerging infectious diseases.

[70]  E. Lander,et al.  Development and Applications of CRISPR-Cas9 for Genome Engineering , 2014, Cell.

[71]  Alexa B. R. McIntyre,et al.  N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection , 2016, Cell host & microbe.

[72]  Jairo Lizarazo,et al.  Guillain-Barré Syndrome Associated with Zika Virus Infection in Colombia. , 2016, The New England journal of medicine.

[73]  M. Vignuzzi,et al.  ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53 , 2016, Cell Death and Disease.

[74]  Wei Zhang,et al.  Structure of Dengue Virus Implications for Flavivirus Organization, Maturation, and Fusion , 2002, Cell.

[75]  E. Datan,et al.  Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication* , 2011, The Journal of Biological Chemistry.

[76]  T. Horvath,et al.  Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection , 2016, Cell.

[77]  M. Ribeiro,et al.  Early Growth and Neurologic Outcomes of Infants with Probable Congenital Zika Virus Syndrome , 2016, Emerging infectious diseases.

[78]  M. Emara,et al.  Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly , 2007, Proceedings of the National Academy of Sciences.

[79]  Justin M. Richner,et al.  Zika Virus Infection in Mice Causes Panuveitis with Shedding of Virus in Tears Graphical Abstract Highlights , 2018 .

[80]  Amadou A. Sall,et al.  The Brazilian Zika virus strain causes birth defects in experimental models , 2016, Nature.

[81]  B. Pulendran,et al.  Zika Virus Infects Human Placental Macrophages. , 2016, Cell host & microbe.

[82]  James E. Crowe,et al.  Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice , 2016, Nature.

[83]  D. Coppola,et al.  Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis , 2015, Nature Communications.

[84]  M. Diamond,et al.  Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise , 2016, Cell.

[85]  Max Endele,et al.  Quantitative single-cell approaches to stem cell research. , 2014, Cell stem cell.

[86]  D. Gubler,et al.  Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness , 2015, Science.

[87]  C. Coyne,et al.  Zika virus — reigniting the TORCH , 2016, Nature Reviews Microbiology.

[88]  G. Dick,et al.  Zika virus. I. Isolations and serological specificity. , 1952, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[89]  K. A. Adams Waldorf,et al.  Influence of infection during pregnancy on fetal development. , 2013, Reproduction.

[90]  David W. Nauen,et al.  Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis. , 2015, Cell stem cell.

[91]  D. Moshfeghi,et al.  Expanded Spectrum of Congenital Ocular Findings in Microcephaly with Presumed Zika Infection. , 2016, Ophthalmology.

[92]  Madeline A. Lancaster,et al.  Cerebral organoids model human brain development and microcephaly , 2013, Nature.

[93]  Jaehoon Shin,et al.  Decoding neural transcriptomes and epigenomes via high-throughput sequencing , 2014, Nature Neuroscience.

[94]  M. Gerstein,et al.  FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders , 2015, Cell.

[95]  Chuan He,et al.  Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. , 2016, Cell host & microbe.

[96]  M. Vignuzzi,et al.  Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses , 2016, Journal of Virology.

[97]  M. Diamond,et al.  A Mouse Model of Zika Virus Pathogenesis. , 2016, Cell host & microbe.

[98]  T. Huisman,et al.  Evidence of Sexual Transmission of Zika Virus , 2016 .

[99]  M. Garcia-Blanco,et al.  G3BP1, G3BP2 and CAPRIN1 Are Required for Translation of Interferon Stimulated mRNAs and Are Targeted by a Dengue Virus Non-coding RNA , 2014, PLoS pathogens.

[100]  M. Vidal,et al.  Hepatitis C virus infection protein network , 2008, Molecular systems biology.

[101]  E. Lavezzo,et al.  Isolation of infectious Zika virus from saliva and prolonged viral RNA shedding in a traveller returning from the Dominican Republic to Italy, January 2016. , 2016, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[102]  Georgia Panagiotakos,et al.  Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells , 2007, Nature Biotechnology.

[103]  Maria Teresa Dell'Anno,et al.  Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. , 2016, Cell reports.

[104]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[105]  M. Garcia-Blanco,et al.  Flavivirus RNA transactions from viral entry to genome replication. , 2016, Antiviral research.

[106]  O. Nascimento,et al.  Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. , 2017, JAMA neurology.

[107]  S. Aguirre,et al.  DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING , 2012, PLoS pathogens.

[108]  Adolfo García-Sastre,et al.  Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling. , 2016, Cell host & microbe.

[109]  Zhiheng Xu,et al.  Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice. , 2016, Cell stem cell.

[110]  A. Perelson,et al.  Zika viral dynamics and shedding in rhesus and cynomolgus macaques , 2016, Nature Medicine.

[111]  G. Ming,et al.  Epigenetic mechanisms in neurogenesis , 2016, Nature Reviews Neuroscience.

[112]  Y. Ohsumi Historical landmarks of autophagy research , 2013, Cell Research.

[113]  E. Huang,et al.  Replication of Hepatitis C Virus RNA on Autophagosomal Membranes* , 2012, The Journal of Biological Chemistry.

[114]  Christopher T. Jones,et al.  Flavivirus Capsid Is a Dimeric Alpha-Helical Protein , 2003, Journal of Virology.

[115]  K. Eggan,et al.  Genetic Ablation of AXL Does Not Protect Human Neural Progenitor Cells and Cerebral Organoids from Zika Virus Infection. , 2016, Cell stem cell.

[116]  G. Ming,et al.  Neural stem cells attacked by Zika virus , 2016, Cell Research.

[117]  E. Harris,et al.  Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. , 2016, Cell host & microbe.

[118]  C. Yip,et al.  Differential cell line susceptibility to the emerging Zika virus: implications for disease pathogenesis, non-vector-borne human transmission and animal reservoirs , 2016, Emerging Microbes & Infections.

[119]  W. Cao,et al.  Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice , 2016, Cell Research.

[120]  N. Heaton,et al.  Dengue virus-induced autophagy regulates lipid metabolism. , 2010, Cell host & microbe.

[121]  S. Cherry,et al.  Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection. , 2016, Cell host & microbe.

[122]  Zhiheng Xu,et al.  Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice. , 2016, Cell stem cell.

[123]  B. Isakson,et al.  AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus. , 2016, Circulation research.

[124]  Jian-Fu Chen,et al.  Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage , 2016, Development.

[125]  David Fenyö,et al.  HIV–host interactome revealed directly from infected cells , 2016, Nature Microbiology.

[126]  C. Blish,et al.  Zika Virus Infection Induces Cranial Neural Crest Cells to Produce Cytokines at Levels Detrimental for Neurogenesis. , 2016, Cell host & microbe.

[127]  G. Ippolito,et al.  Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016 , 2016, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[128]  L. Bavia,et al.  A glance at subgenomic flavivirus RNAs and microRNAs in flavivirus infections , 2016, Virology Journal.

[129]  T. Pierson,et al.  A CRISPR screen defines a signal peptide processing pathway required by flaviviruses , 2016, Nature.