Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6

• DOI: 10.1038/icb.2017.5
• Publication Date: 2017-02-21T14:16:42Z
• Authors: Naphak Modhiran; Daniel Watterson; Antje Blumenthal; Alan G Baxter; Paul R Young; Katryn J Stacey
• Keywords: Lipopolysaccharides; 0301 basic medicine; 2403 Immunology; 570; Immunology; 610; 500; Cell Biology; Dengue Virus; Viral Nonstructural Proteins; Toll-Like Receptor 2; 3. Good health; 1307 Cell Biology; Mice, Inbred C57BL; Toll-Like Receptor 4; 03 medical and health sciences; Toll-Like Receptor 6; Escherichia coli; Leukocytes; Animals; Humans; Protein Multimerization; Polymyxin B

The secreted hexameric form of the dengue virus (DENV) non-structural protein 1 (NS1) has recently been shown to elicit inflammatory cytokine release and disrupt endothelial cell monolayer integrity. This suggests that circulating NS1 contributes vascular leak plays a major role in pathology haemorrhagic fever shock. Pathways activated by are thus great interest as potential therapeutic targets. Recent works have separately implicated both toll-like receptor 4 (TLR4) TLR2/6 heterodimer immune activation NS1. Here we used mouse gene knockout macrophages antibodies blocking TLR function human peripheral blood mononuclear cells show recombinant NS1, expressed purified from eukaryotic cells, induces production via TLR4 but not TLR2/6. Furthermore, commercial Escherichia coli-derived preparation other work implicate response is correctly folded appears be contaminated several microbial ligands. Thus remains target for DENV infections, with antagonists holding promise treatment disease.