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Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.

ABSTRACT: Dengue virus (DENV) nonstructural protein-1 (NS1) is a secreted glycoprotein that is absent from viral particles but accumulates in the supernatant and on the plasma membrane of cells during infection. Immune recognition of cell surface NS1 on endothelial cells has been hypothesized as a mechanism for the vascular leakage that occurs during severe DENV infection. However, it has remained unclear how NS1 becomes associated with the plasma membrane, as it contains no membrane-spanning sequence motif. Using flow cytometric and ELISA-based binding assays and mutant cell lines lacking selective glycosaminoglycans, we show that soluble NS1 binds back to the surface of uninfected cells primarily via interactions with heparan sulfate and chondroitin sulfate E. DENV NS1 binds directly to the surface of many types of epithelial and mesenchymal cells yet attaches poorly to most peripheral blood cells. Moreover, DENV NS1 preferentially binds to cultured human microvascular compared to aortic or umbilical cord vein endothelial cells. This binding specificity was confirmed in situ as DENV NS1 bound to lung and liver but not intestine or brain endothelium of mouse tissues. Differential binding of soluble NS1 by tissue endothelium and subsequent recognition by anti-NS1 antibodies could contribute to the selective vascular leakage syndrome that occurs during severe secondary DENV infection.

SUBMITTER: Avirutnan P

PROVIDER: S-EPMC2092380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundExfoliative glaucoma (XFG) is typically classified as a high-pressure type of secondary open-angle glaucoma that develops as a consequence of exfoliation syndrome (XFS). Exfoliation syndrome is an age-related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar exfoliation material (XFM) in intra- and extraocular tissues. Exfoliation material represents complex glycoprotein/proteoglycan structure composed of a protein core surrounded by glycosaminoglycans such as heparan sulfate (HS) and chondroitin sulfate (CS). The purpose of the present study was to investigate HS and CS concentrations in serum samples of patients with newly diagnosed XFG and compare the obtained values with those pertaining to newly diagnosed primary open-angle glaucoma (POAG), normal controls (NC) and subjects with XFS.MethodsThis case-control study involved 165 subjects, including patients with newly diagnosed XFG, patients with newly diagnosed POAG, subjects with XFS and age- and sex-matched NC. The study was conducted at the Glaucoma Department of Clinic for Eye Diseases, Clinical Centre of Serbia, as the referral center for glaucoma in Serbia.ResultsThe mean age in the XFG, POAG, XFS and NC groups was 73.3 ± 9.0, 66.3 ± 7.8, 75.5 ± 7.0 and 73.5 ± 9.5 years, respectively, XFG vs. POAG, p < 0.001. Mean serum HS concentrations in the XFG, POAG, NC and XFS groups were 3,189.0 ± 1,473.8 ng/mL, 2,091.5 ± 940.9 ng/mL, 2,543.1 ± 1,397.3 ng/mL and 2,658.2 ± 1,426.8 ng/mL respectively, XFG vs. POAG, p = 0.001 and XFG vs. NC, p = 0.032. Mean serum CS concentrations in the XFG, POAG, NC and XFS group were 43.9 ± 20.7 ng/mL, 38.5 ± 22.0 ng/mL, 35.8 ± 16.4 ng/mL and 43.3 ± 21.8 ng/mL, respectively, XFG vs. NC, p = 0.041.ConclusionsOur findings revealed greater HS and CS concentrations in XFG patients and XFS subjects compared to those without XFM. Implications of HS and CS in the pathophysiology of XFS and glaucoma should be studied further. Serum is easily accessible and should thus be explored as rich sources of potential biomarkers. Further research should aim to identify XFG biomarkers that could be utilized in routine blood analysis tests, aiding in timely disease diagnosis.

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Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.

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