Abstract
Dengue fever is a rapidly emerging vector-borne viral disease with a growing global burden of approximately 390 million new infections per annum. The Dengue virus (DENV) is a flavivirus spread by female mosquitos of the aedes genus, but the mechanism of viral endocytosis is poorly understood at a molecular level, preventing the development of effective transmission blocking vaccines (TBVs). Recently, glycosaminoglycans (GAGs) have been identified as playing a role during initial viral attachment through interaction with the third domain of the viral envelope protein (EDIII). Here, we report a systematic study investigating the effect of a range of biologically relevant GAGs on the structure and oligomeric state of recombinantly generated EDIII. We provide novel in situ biophysical evidence that heparin and chondroitin sulphate C induce conformational changes in EDIII at the secondary structure level. Furthermore, we report the ability of chondroitin sulphate C to bind EDIII and induce higher-order dynamic molecular changes at the tertiary and quaternary structure levels which are dependent on pH, GAG species, and the GAG sulphation state. Lastly, we conducted ab initio modelling of Small Angle Neutron Scattering (SANS) data to visualise the induced oligomeric state of EDIII caused by interaction with chondroitin sulphate C, which may aid in TBV development.
Highlights
Dengue virus (DENV) causes the world’s most prevalent mosquito-borne flavivirus (FLV) disease, placing 3.9 billion people at risk of infection and resulting in approximately 20 million cases each year in 129 countries around the tropics and subtropics [1,2]
Our findings provide evidence for binding of the Dengue envelope protein to GAGs and will be invaluable in understanding molecular interactions occurring in the initial phase of host recognition by the virus, which is important for developing effective transmission blocking vaccines (TBVs) that target this initial interaction event
Heparan sulphate, a lesser sulphated derivative of heparin, was unable to induce the secondary structure changes observed with heparin, demonstrating the importance of sulphation state and sulphate group positioning as a prerequisite for ensuring specific charge density and distribution on the polysaccharide, which in turn mediate specific interactions between GAGs and viral envelope proteins
Summary
Dengue virus (DENV) causes the world’s most prevalent mosquito-borne flavivirus (FLV) disease, placing 3.9 billion people at risk of infection and resulting in approximately 20 million cases each year in 129 countries around the tropics and subtropics [1,2]. The mechanism by which DENV infects its target host cell is the major determinant of the virus cellular tropism and is critical for viral pathogenesis. Glycosaminoglycans (GAGs) are thought to be the initial co-receptors that all pathogenic FLVs utilise for the infection of host cells [4,5,6], which is followed by interaction with protein-based receptors [7]. FLVs infiltrate the host cell through clathrin-mediated or independent endocytosis, accompanied by a pH-dependent conformational change in the envelope protein, and followed by membrane fusion and the release of the viral genome into the cell [8]
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