THE ROLE OF GENETIC VARIANTS OF NON-STRUCTURAL PROTEIN 1 IN DENGUE PATHOGENESIS

Abstract

The secreted form of dengue non-structural protein 1 (sNS1) can cause vascular leakage, a hallmark of severe disease. This work explored several genetic variants of NS1 present in the viral population with an emphasis on T164S mutation that has been associated with increased intraepidemic disease severity to understand the role of NS1 in virus replication and disease pathogenesis. The T164S mutant virus (TS-virus) infection resulted in reduced virus production and increased sNS1 production in various cell lines and human PBMCs without affecting viral-RNA replication. Infection of AG129 mice displayed severe symptoms coupled with enhanced complement activation, tissue inflammation and higher lethality. Lipidomics profiling of the purified sNS1 from wild-type and TS-virus revealed that they carried different lipid classes. Interestingly, treatment of human PBMCs with purified sNS1 from TS-virus resulted in higher pro-inflammatory cytokines production, revealing that the structural/physical properties of sNS1 could be a contributing factor in disease severity.