| Literature DB >> 32402284 |
Milly M Choy1, Dorothy H L Ng2, Tanamas Siriphanitchakorn3, Wy Ching Ng1, Karin B Sundstrom1, Hwee Cheng Tan1, Summer L Zhang1, Kitti W K Chan1, Menchie Manuel1, R Manjunatha Kini4, Kuan Rong Chan1, Subhash G Vasudevan5, Eng Eong Ooi6.
Abstract
The molecular basis of dengue virus (DENV) attenuation remains ambiguous and hampers a targeted approach to derive safe but nonetheless immunogenic live vaccine candidates. Here, we take advantage of DENV serotype 2 PDK53 vaccine strain, which recently and successfully completed a phase-3 clinical trial, to identify how this virus is attenuated compared to its wild-type parent, DENV2 16681. Site-directed mutagenesis on a 16681 infectious clone identifies a single G53D substitution in the non-structural 1 (NS1) protein that reduces 16681 infection and dissemination in both Aedes aegypti, as well as in mammalian cells to produce the characteristic phenotypes of PDK53. Mechanistically, NS1 G53D impairs the function of a known host factor, the endoplasmic reticulum (ER)-resident ribophorin 1 protein, to properly glycosylate NS1 and thus induce a host antiviral gene through ER stress responses. Our findings provide molecular insights on DENV attenuation on a clinically tested strain.Entities:
Keywords: Aedes aegypti; Dengue; ER stress; NS1; PDK53; RPN1; interferon; plaque size; ribophorin 1; vaccine
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Year: 2020 PMID： 32402284 DOI： 10.1016/j.celrep.2020.107617
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423