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Zika viruses encode 5′ upstream open reading frames affecting infection of human brain cells

Author

Listed:
  • Charlotte Lefèvre

    (University of Cambridge)

  • Georgia M. Cook

    (University of Cambridge)

  • Adam M. Dinan

    (University of Cambridge
    University of Cambridge)

  • Shiho Torii

    (Insect-Virus Interactions Unit)

  • Hazel Stewart

    (University of Cambridge)

  • George Gibbons

    (University of Cambridge)

  • Alex S. Nicholson

    (University of Cambridge)

  • Liliana Echavarría-Consuegra

    (University of Cambridge)

  • Luke W. Meredith

    (University of Cambridge)

  • Valeria Lulla

    (University of Cambridge)

  • Naomi McGovern

    (University of Cambridge)

  • Julia C. Kenyon

    (University of Cambridge)

  • Ian Goodfellow

    (University of Cambridge)

  • Janet E. Deane

    (University of Cambridge)

  • Stephen C. Graham

    (University of Cambridge)

  • András Lakatos

    (University of Cambridge
    Cambridge Stem Cell Institute)

  • Louis Lambrechts

    (Insect-Virus Interactions Unit)

  • Ian Brierley

    (University of Cambridge)

  • Nerea Irigoyen

    (University of Cambridge)

Abstract

Zika virus (ZIKV), an emerging mosquito-borne flavivirus, is associated with congenital neurological complications. Here, we investigate potential pathological correlates of virus gene expression in representative ZIKV strains through RNA sequencing and ribosome profiling. In addition to the single long polyprotein found in all flaviviruses, we identify the translation of unrecognised upstream open reading frames (uORFs) in the genomic 5′ region. In Asian/American strains, ribosomes translate uORF1 and uORF2, whereas in African strains, the two uORFs are fused into one (African uORF). We use reverse genetics to examine the impact on ZIKV fitness of different uORFs mutant viruses. We find that expression of the African uORF and the Asian/American uORF1 modulates virus growth and tropism in human cortical neurons and cerebral organoids, suggesting a potential role in neurotropism. Although the uORFs are expressed in mosquito cells, we do not see a measurable effect on transmission by the mosquito vector in vivo. The discovery of ZIKV uORFs sheds new light on the infection of the human brain cells by this virus and raises the question of their existence in other neurotropic flaviviruses.

Suggested Citation

  • Charlotte Lefèvre & Georgia M. Cook & Adam M. Dinan & Shiho Torii & Hazel Stewart & George Gibbons & Alex S. Nicholson & Liliana Echavarría-Consuegra & Luke W. Meredith & Valeria Lulla & Naomi McGover, 2024. "Zika viruses encode 5′ upstream open reading frames affecting infection of human brain cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53085-9
    DOI: 10.1038/s41467-024-53085-9
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    References listed on IDEAS

    as
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