Knock, knock, who’s there? Investigating the cellular mode of entry of Zika virus


Think Brazil, think Olympics, rain forests, soccer, beaches and carnival. But now a more insidious association comes to mind – the dreaded Zika virus. An arbovirus of the Flaviviridae family, which includes dengue, yellow fever, West Nile and Japanese encephalitis viruses, Zika virus was first described in 1947. Recently, Zika virus has gained a strong foothold in Central and South America and the latest outbreak in Brazil has been linked with significant increases in fetal abnormalities and microcephaly. Declared a global health emergency by the World Health Organization (2), the ability of Zika virus to cross the human fetal-placental barrier and infect the developing central nervous system has also been established (1, 3, 4).

The Zika virus is transmitted by the Aedes mosquito, but how does it gain entry into cells? A recent study by Nowakowski et al. (1) investigated the expression of receptors implicated in cell entry of Zika virus in diverse cell types in the developing brain. By employing single cell RNA-seq and immunohistochemistry, the authors found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells and microglia in the developing human cortex and by progenitor cells in developing retina, indicating that these cell types are particularly susceptible to Zika virus infection. The research suggests that after breaching the placental-fetal barrier, Zika virus reaches the developing brain either by hematogenous spread or via cerebrospinal fluid and invades radial glia cells. By preferentially destroying radial glia cells, Zika virus can result in severe microcephaly. Further research is required to establish whether AXL expression alone determines the cellular population with enhanced neurotropism for Zika virus in the developing human brain or whether other binding factors, including genes expressed at low levels, are involved. As the expression of AXL in radial glia is found to be conserved in the developing mouse and ferret cortex and in human stem cell-derived cerebral organoids, multiple experimental models can be employed to investigate the effects of Zika virus infection on brain development.

What is AXL receptor tyrosine kinase? A member of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase subfamily, AXL receptor tyrosine kinase transduces signals from the extracellular matrix into the cytoplasm by binding to the vitamin K-dependent protein growth arrest-specific 6 (Gas6). Digital RNA-seq is an invaluable tool for quantitative transcriptional profiling of genes like AXL.

Are there any other tyrosine kinase receptors involved in the process of cellular entry by Zika virus? Understanding the molecular basis of the host’s response to Zika virus infection is fundamental in the development of treatments and vaccines in the fight against Zika virus. Targeted sequencing approaches allow you to focus your sequencing capacity on clinically important targets. Which genes should be included in a custom gene panel to determine the host response?  Is there a specific group of genes you would like to study (add your comments in the discussion box)? For more information, visit the GeneGlobe portal, where you can find details on custom panel design and discover tools like the QIAseq Targeted RNA Virtual Panels, which allow digital RNA-seq for gene expression profiling of genes like AXL. To decipher the transcriptional profile of single cells, explore our single cell RNA-seq solutions.



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  1. 1. Calvet, G. et al. (2016) Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect. Dis. 16, 653–660 (Link)
  2. 2. Heymann, D.L. et al. (2016) Zika virus and microcephaly: why is this situation a PHEIC?. Lancet. 387, 719–721 (Link)
  3. 3. Martines, R.B. et al. (2016) Notes from the field: Evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses – Brazil, 2015. MMWR Morb. Mortal. Wkly. Rep. 65, 159–160 (Link)
  4. 4. Mlakar, J. et al. (2016) Zika virus associated with microcephaly. N. Engl. J. Med. 374, 951–958 (Link)
  5. 5. Nowakowski, T. J. et al. (2016) Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 18, 591–596 (Link)
Devika Mathur

Devika Mathur is a Senior Technical & Marketing Writer at QIAGEN. Devika joined QIAGEN in 2008 and has been responsible for creating literature for numerous QIAGEN products, including the REPLI-g and QIAseq product lines, and has written extensively on various scientific topics ranging from next-generation sequencing and single cell analysis to PCR and sample preparation. Devika is a graduate from University College Cork, Ireland, and has a microbiology research background, focusing primarily on the molecular characterization of the replication module of the lactococcal bacteriophage Tuc2009.

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