Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling

Abstract

Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain–Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3,4,5,6,7,8,9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10,11,12,13,14,15,16,17,18,19,20,21,22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: AXL knockout prevents productive ZIKV infection in human astrocytes.
Fig. 2: AXL knockout does not block ZIKV entry but protects astrocytes via an IFNAR signalling-dependent mechanism.
Fig. 3: AXL antagonizes type I IFN signalling during ZIKV infection via an SOCS1-dependent mechanism.
Fig. 4: Mechanism of AXL-SOCS1 negative regulation of type I IFN signalling.

References

  1. 1.

    Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro. N. Engl. J. Med. 375, 2321–2334 (2016).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Parra, B. et al. Guillain-Barre syndrome associated with Zika virus infection in Colombia. N. Engl. J. Med. 375, 1513–1523 (2016).

    PubMed  Google Scholar 

  3. 3.

    Tang, H. et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).

    CAS  PubMed  Google Scholar 

  5. 5.

    Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Miner, J. J. et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 165, 1081–1091 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Li, H. et al. Zika virus infects neural progenitors in the adult mouse brain and alters proliferation. Cell Stem Cell 19, 593–598 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Adams Waldorf, K. M. et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat. Med. 22, 1256–1259 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Meertens, L. et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe 12, 544–557 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Miner, J. J. et al. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nat. Med. 21, 1464–1472 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hamel, R. et al. Biology of Zika Virus infection in human skin cells. J. Virol. 89, 8880–8896 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Retallack, H. et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl Acad. Sci. USA 113, 14408–14413 (2016).

    CAS  PubMed  Google Scholar 

  14. 14.

    Savidis, G. et al. Identification of Zika virus and Dengue virus dependency factors using functional genomics. Cell Rep. 16, 232–246 (2016).

    CAS  PubMed  Google Scholar 

  15. 15.

    Nowakowski, T. J. et al. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 18, 591–596 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Tabata, T. et al. Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission. Cell Host Microbe 20, 155–166 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Ma, W. et al. Zika virus causes testis damage and leads to male infertility in mice. Cell 167, 1511–1524 (2016).

    CAS  PubMed  Google Scholar 

  18. 18.

    Wells, M. F. et al. Genetic ablation of AXL does not protect human neural progenitor cells and cerebral organoids from Zika virus infection. Cell Stem Cell 19, 703–708 (2016).

    CAS  PubMed  Google Scholar 

  19. 19.

    Miner, J. J. et al. Zika virus infection in mice causes panuveitis with shedding of virus in tears. Cell Rep. 16, 3208–3218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hastings, A. K. et al. TAM receptors are not required for Zika virus infection in mice. Cell Rep. 19, 558–568 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Li, F. et al. AXL is not essential for Zika virus infection in the mouse brain. Emerg. Microbes Infect. 6, e16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Govero, J. et al. Zika virus infection damages the testes in mice. Nature 540, 438–442 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Grant, A. et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882–890 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kumar, A. et al. Zika virus inhibits type-I interferon production and downstream signaling. EMBO Rep. 17, 1766–1775 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Khan, S. et al. Dampened antiviral immunity to intravaginal exposure to RNA viral pathogens allows enhanced viral replication. J. Exp. Med. 213, 2913–2929 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Meertens, L. et al. Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell Rep. 18, 324–333 (2017).

    CAS  PubMed  Google Scholar 

  27. 27.

    Rausch, K. et al. Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus. Cell Rep. 18, 804–815 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Liu, S., DeLalio, L. J., Isakson, B. E. & Wang, T. T. AXL-mediated productive infection of human endothelial cells by Zika virus. Circ. Res. 119, 1183–1189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lindqvist, R. et al. Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. J. Neuroinflamm. 13, 277 (2016).

    Google Scholar 

  30. 30.

    Hussmann, K. L., Vandergaast, R., Zheng, K., Hoover, L. I. & Fredericksen, B. L. Structural proteins of West Nile virus are a major determinant of infectious particle production and fitness in astrocytes. J. Gen. Virol. 95, 1991–2003 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Hussmann, K. L., Samuel, M. A., Kim, K. S., Diamond, M. S. & Fredericksen, B. L. Differential replication of pathogenic and nonpathogenic strains of West Nile virus within astrocytes. J. Virol. 87, 2814–2822 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Palus, M. et al. Infection and injury of human astrocytes by tick-borne encephalitis virus. J. Gen. Virol. 95, 2411–2426 (2014).

    PubMed  Google Scholar 

  33. 33.

    van den Pol, A. N., Mao, G., Yang, Y., Ornaghi, S. & Davis, J. N. Zika virus targeting in the developing brain. J. Neurosci. 37, 2161–2175 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Deng, Y. Q. et al. Isolation, identification and genomic characterization of the Asian lineage Zika virus imported to China. Sci. China Life Sci. 59, 428–430 (2016).

    PubMed  Google Scholar 

  35. 35.

    Perera-Lecoin, M., Meertens, L., Carnec, X. & Amara, A. Flavivirus entry receptors: an update. Viruses 6, 69–88 (2014).

    Google Scholar 

  36. 36.

    Sasaki, T. et al. Structural basis for Gas6-Axl signalling. EMBO J. 25, 80–87 (2006).

    CAS  PubMed  Google Scholar 

  37. 37.

    Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B. & Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124–1136 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bhattacharyya, S. et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14, 136–147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Porritt, R. A. & Hertzog, P. J. Dynamic control of type I IFN signalling by an integrated network of negative regulators. Trends Immunol. 36, 150–160 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Yockey, L. J. et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell 166, 1247–1256 e1244 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lazear, H. M. et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe 19, 720–730 (2016).

    CAS  Google Scholar 

  42. 42.

    Cho, H., Shrestha, B., Sen, G. C. & Diamond, M. S. A role for IFIT2 in restricting West Nile virus infection in the brain. J. Virol. 87, 8363–8371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Wang, Z. Y. et al. Axl is not an indispensable factor for Zika virus infection in mice. J. Gen. Virol. 98, 2061–2068 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Jagger, B. W. et al. Gestational stage and IFN-λ signaling regulate ZIKV infection in utero. Cell Host Microbe 22, 366–376 e363 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Wu, T. D. & Nacu, S. Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26, 873–881 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    CAS  Google Scholar 

  47. 47.

    Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).

    Google Scholar 

  49. 49.

    Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: A tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinform. 10, 48 (2009).

    Google Scholar 

  50. 50.

    Supek, F., Bosnjak, M., Skunca, N. & Smuc, T. REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS ONE 6, e21800 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Cheadle, C., Vawter, M. P., Freed, W. J. & Becker, K. G. Analysis of microarray data using Z score transformation. J. Mol. Diagn. 5, 73–81 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Foundation of China (81430030 to J.X.), the ShanghaiTech University Startup Fund (to B.J. and J.L.), the Shanghai Public Health Clinical Center (to X.Z.), the Developmental Center of Shanghai Shenkang Hospital (SHDC12014104 to X.Z.) and the Shanghai Advanced Biosafety and Pathogen Diagnostic Platform (15DZ2290200 to X.Z.).

Author information

Affiliations

Authors

Contributions

J.X. and J.L. conceived this study. Jian C., Y.-F.Y., B.J., X.Z., J.L. and J.X. designed the experiments. Jian C., Y.-F.Y., Y.Y., Yongquan H., S.-L.S., Y.-R.C., R.B., Y.-J.L. and J.L. performed the experiments. P.Z., Yunwen H. and L.L. prepared the ZIKV. Jun C. analysed the RNA-Seq data. Jian C., Y.-F.Y., J.L. and J.X. prepared the manuscript.

Corresponding authors

Correspondence to Xiaoyan Zhang or Jia Liu or Jianqing Xu.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–11, Supplementary Table 1 and Supplementary Notes.

Life Sciences Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Yang, Yf., Yang, Y. et al. AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling. Nat Microbiol 3, 302–309 (2018). https://doi.org/10.1038/s41564-017-0092-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing