CryoEM structures of the multimeric secreted NS1, a major factor for dengue hemorrhagic fever

Journal article

Mosquito-borne Zika virus (ZIKV) from sub-Saharan Africa has recently gained attention due to its epidemic potential and its capacity to be highly teratogenic. To improve our knowledge on currently circulating strains of African ZIKV, we conducted protein sequence alignment and identified contemporary West Africa NS1 (NS1CWA) protein as a highly conserved viral protein. Comparison of NS1CWA with the NS1 of the historical African ZIKV strain MR766 (NS1MR766), revealed seven amino acid substitutions. The effects of NS1 mutations on protein expression, virus replication, and innate immune activation were assessed in human cells using recombinant NS1 proteins and a chimeric viral clone MR766 with NS1CWA replacing NS1MR766. Our data indicated higher secretion efficiency of NS1CWA compared to NS1MR766 associated with a change in subcellular distribution. A chimeric MR766 virus with NS1CWA instead of authentic protein displayed a greater viral replication efficiency, leading to more pronounced cell death compared to parental virus. Enhanced viral growth was associated with reduced activation of innate immunity. Our data raise questions of the importance of NS1 protein in the pathogenicity of contemporary ZIKV from sub-Saharan Africa and point to differences within viral strains of African lineage

Authors: Shu, B; Ooi, JSG; Tan, AWK; Ng, T-S; Dejnirattisai, W

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 6756-6756
• Article number: 6756
• Publication date: 2022-11-08
• DOI: 10.1038/s41467-022-34415-1
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Extracellular; Biology; Enzyme; Recombinant DNA; Intracellular; Cell biology; Protein structure; Tetramer; Chemistry; Biochemistry; Dengue fever; Virology; Dengue virus