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

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.

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Publication Details

Journal
Nature Communications
Published
2024-10-12
DOI
https://doi.org/10.1038/s41467-024-53085-9
Citations
10
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
4.89

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article

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

Julia C. Kenyon, Nerea Irigoyen, George M. Gibbons, Ian Brierley et al.
10 citations
Nature Communications
Mosquito-borne diseases and control
4.89
article

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

Julia C. Kenyon, Nerea Irigoyen, George M. Gibbons, Ian Brierley, Ian Goodfellow, Valeria Lulla, Liliana Echavarría-Consuegra, Georgia M. Cook, András Lakatos, Naomi McGovern, Adam M. Dinan, Alex S. Nicholson, Janet Elwyn Deane, Stephen C. Graham, Louis Lambrechts, Shiho Torii, Charlotte Lefèvre, Hazel Stewart, Luke W. Meredith
article en
10 citations

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.

Nature CommunicationsVol. 15(1)
Centre National de la Recherche Scientifique (FR), Institut Pasteur (FR), MRC Laboratory of Molecular Biology (GB), Université Paris Cité (FR), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB)
Wellcome Trust, UK Research and Innovation, International Seafood Sustainability Foundation, University College London, European Commission, Agence Nationale de la Recherche, Isaac Newton Trust, Tartu Ülikool, National Institutes of Health, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 4%
Mosquito-borne diseases and control
4.89
DOIOpen Access PDFOpenAlex
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