Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis

All flaviviruses, including Zika virus, produce noncoding subgenomic flaviviral RNA (sfRNA), which plays an important role in viral pathogenesis. However, the exact mechanism of how sfRNA enables viral evasion of antiviral response is not well defined. Here, we show that sfRNA is required for transp...

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Published inScience advances Vol. 8; no. 48; p. eadd8095
Main Authors Slonchak, Andrii, Wang, Xiaohui, Aguado, Julio, Sng, Julian D J, Chaggar, Harman, Freney, Morgan E, Yan, Kexin, Torres, Francisco J, Amarilla, Alberto A, Balea, Rickyle, Setoh, Yin Xiang, Peng, Nias, Watterson, Daniel, Wolvetang, Ernst, Suhrbier, Andreas, Khromykh, Alexander A
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 02.12.2022
Subjects
Animals
Antiviral Agents
Biomedicine and Life Sciences
Female
Humans
Mice
Molecular Biology
Phosphorylation
Placenta
Pregnancy
RNA, Untranslated - genetics
RNA, Viral - genetics
SciAdv r-articles
STAT1 Transcription Factor - genetics
Viral Proteins
Virology
Zika Virus
Zika Virus Infection - genetics
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Summary:All flaviviruses, including Zika virus, produce noncoding subgenomic flaviviral RNA (sfRNA), which plays an important role in viral pathogenesis. However, the exact mechanism of how sfRNA enables viral evasion of antiviral response is not well defined. Here, we show that sfRNA is required for transplacental virus dissemination in pregnant mice and subsequent fetal brain infection. We also show that sfRNA promotes apoptosis of neural progenitor cells in human brain organoids, leading to their disintegration. In infected human placental cells, sfRNA inhibits multiple antiviral pathways and promotes apoptosis, with signal transducer and activator of transcription 1 (STAT1) identified as a key shared factor. We further show that the production of sfRNA leads to reduced phosphorylation and nuclear translocation of STAT1 via a mechanism that involves sfRNA binding to and stabilizing viral protein NS5. Our results suggest the cooperation between viral noncoding RNA and a viral protein as a novel strategy for counteracting antiviral responses.
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These authors contributed equally to this work as co–senior authors.
Present address: Health and Biosecurity, Commonwealth Scientific and Industrial Research Organization, Acton, ACT, Australia.
Present address: Microbiology and Molecular Epidemiology Division, Environmental Health Institute, National Environmental Agency, Singapore, Singapore.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.add8095