The dengue virus NS1 protein; new roles in pathogenesis due to similarities with and affinity for the high-density lipoprotein (HDL)?
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ABSTRACT:
SUBMITTER: Alcala AC
PROVIDER: S-EPMC10449462 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Publications
The dengue virus NS1 protein; new roles in pathogenesis due to similarities with and affinity for the high-density lipoprotein (HDL)?
Alcalá Ana C AC Ludert Juan E JE
PLoS pathogens 20230824 8
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Project description:Dengue virus (DENV) causes the major arboviral disease of the tropics, characterized in its severe forms by signs of hemorrhage and plasma leakage. DENV encodes a nonstructural glycoprotein, NS1, that associates with intracellular membranes and the cell surface. NS1 is eventually secreted as a soluble hexamer from DENV-infected cells and circulates in the bloodstream of infected patients. Extracellular NS1 has been shown to modulate the complement system and to enhance DENV infection, yet its structure and function remain essentially unknown. By combining cryoelectron microscopy analysis with a characterization of NS1 amphipathic properties, we show that the secreted NS1 hexamer forms a lipoprotein particle with an open-barrel protein shell and a prominent central channel rich in lipids. Biochemical and NMR analyses of the NS1 lipid cargo reveal the presence of triglycerides, bound at an equimolar ratio to the NS1 protomer, as well as cholesteryl esters and phospholipids, a composition evocative of the plasma lipoproteins involved in vascular homeostasis. This study suggests that DENV NS1, by mimicking or hijacking lipid metabolic pathways, contributes to endothelium dysfunction, a key feature of severe dengue disease.
| S-EPMC3093454 | biostudies-literature
Project description:To identify the interaction of Dengue virus non-structural protein (NS1) with high-affinity antibody.
2024-04-30 | PXD042235 | Pride
Project description:We report changes in gene expression in the Burkitt's lymphoma cell line Ramos, treated with high density lipoprotein-like nanoparticles (HDL NPs) for 48 hours, compared to saline (NT) and natural, human HDL treatment
2019-04-20 | GSE98028 | GEO
Project description:There is extensive evidence demonstrating that there is a clear inverse correlation between plasma high density lipoprotein cholesterol (HDL-C) concentration and cardiovascular disease (CVD). On the other hand, there is also extensive evidence that HDL functionality plays a very important role in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for the metabolism and adequate function of HDL, may positively or negatively affect the HDL-C levels and/or HDL functionality and subsequently either provide protection or predispose to atherosclerotic disease. This review aims to describe certain genetic disorders associated with either low or high plasma HDL-C and discuss their clinical features, associated risk for cardiovascular events, and treatment options.
| S-EPMC6135231 | biostudies-literature
Project description:Cross-linking mass spectrometry was performed on 1) wild-type secreted dengue virus (DENV2) sNS1 protein with bovine ApoA1 (major component of high-density lipoprotein)
and 2) mutant (T164S) sNS1 protein with bovine ApoA1
2023-11-11 | PXD038097 | JPOST Repository
Project description:BackgroundThough the previous genome-wide association studies found the association between HLA alleles and rosacea in the European populations, the data is lacking among the Asians. Moreover, neutrophils are important in the immune-related mechanism of rosacea, and dyslipidemia is closely related to rosacea. We aimed to explore the association between HLA genes and rosacea in Chinese rosacea patients, as well as the mediation effect of neutrophils, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) on the relationship between HLA genes and rosacea.MethodsA total of 249 rosacea and 150 controls were ranked by the international investigator global rosacea severity scores. HLA genes, neutrophils, HDL, and LDL were detected. And their mediation effects on the relationship between HLA and rosacea risk or severity were analysed.ResultsHLA-DQB1*03:03 allele (OR = 41.89, 95% CI: 9.80 ∼ 179.09, p = 4.7*10-7), HLA-DQB1*04:02 allele (OR = 0.16, 95% CI: 0.03 ∼ 0.81, p = 0.026) and HLA-DQB1*03:03/05:02 genotype (OR = 5.57, 95% CI: 1.13 ∼ 27.52, p = 0.0351) were significantly associated with rosacea. Moreover, HLA-DQB1*03:03 allele (b = 1.434, SE = 0.217, p = 2.0*10-10), HLA-DQB1*05:01 allele (b = 0.894, SE = 0.33520, p = 0.008) and HLA-DQB1*03:03/06:01 genotype (b = 0.998, SE = 0.472, p = 0.040) were positively associated with rosacea severity. Furthermore, we found both neutrophils and HDL, instead of LDL, have mediation effects on the relationship between HLA-DQB1*03:03 and risk or severity of rosacea.ConclusionsWe discovered novel susceptible HLA alleles for rosacea in the Chinese population, and disclosed the mediation effect of neutrophils and HDL on the relationship between HLA-DQB1 and rosacea, implying a possible correlation between rosacea and inflammatory or metabolic factors, providing hints for future studies in the mechanism of rosacea. Key messagesHLA-DQB1*03:03 allele, HLA-DQB1*04:02 allele and HLA-DQB1*03:03/05:02 genotype were significantly associated with rosacea.HLA-DQB1*03:03 allele, HLA-DQB1*05:01 allele and HLA-DQB1*03:03/06:01 genotype were positively associated with rosacea severity.Neutrophils and HDL have mediation effects on the relationship between HLA-DQB1*03:03 and risk or severity of rosacea.
| S-EPMC9891224 | biostudies-literature
Project description:Objective- HDL (high-density lipoprotein) in plasma is a heterogeneous group of lipoproteins typically containing apo AI as the principal protein. Most HDLs contain additional proteins from a palate of nearly 100 HDL-associated polypeptides. We hypothesized that some of these proteins define distinct and stable apo AI HDL subspecies with unique proteomes that drive function and associations with disease. Approach and Results- We produced 17 plasma pools from 80 normolipidemic human participants (32 men, 48 women; aged 21-66 years). Using immunoaffinity isolation techniques, we isolated apo AI containing species from plasma and then used antibodies to 16 additional HDL protein components to isolate compositional subspecies. We characterized previously described HDL subspecies containing apo AII, apo CIII, and apo E; and 13 novel HDL subspecies defined by presence of apo AIV, apo CI, apo CII, apo J, α-1-antitrypsin, α-2-macroglobulin, plasminogen, fibrinogen, ceruloplasmin, haptoglobin, paraoxonase-1, apo LI, or complement C3. The novel species ranged in abundance from 1% to 18% of total plasma apo AI. Their concentrations were stable over time as demonstrated by intraclass correlations in repeated sampling from the same participants over 3 to 24 months (0.33-0.86; mean 0.62). Some proteomes of the subspecies relative to total HDL were strongly correlated, often among subspecies defined by similar functions: lipid metabolism, hemostasis, antioxidant, or anti-inflammatory. Permutation analysis showed that the proteomes of 12 of the 16 subspecies differed significantly from that of total HDL. Conclusions- Taken together, correlation and permutation analyses support speciation of HDL. Functional studies of these novel subspecies and determination of their relation to diseases may provide new avenues to understand the HDL system of lipoproteins.
| S-EPMC6309805 | biostudies-literature
Project description:Objective- HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause. Approach and Results- Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61.8±10.3; 61% natural-, 21% surgical-, and 18% peri-menopause). Women with unknown or early menopause (age at nonsurgical menopause ≤45 years) were excluded. Adjusting for each other, higher HDL-P but not HDL-C was associated with lower cIMT ( P=0.001), whereas higher HDL-C but not HDL-P was associated with greater risk of carotid plaque presence ( P=0.04). Time since menopause significantly modified the association of large but not small HDL-P with cIMT; higher large HDL-P was associated with higher cIMT close to menopause but with lower cIMT later in life. The proatherogenic association reported for HDL-C with carotid plaque was most evident in women with later age at menopause who were >10 years postmenopausal. Conclusions- Elevated HDL-C may not always be cardioprotective in postmenopausal women. The cardioprotective capacity of large HDL-P may adversely compromise close to menopause supporting the importance of assessing how the menopause transition might impact HDL quality and related cardiovascular disease risk later in life.
| S-EPMC6202150 | biostudies-literature
Project description:The role of NS1-specific antibodies in the pathogenesis of dengue virus infection is poorly understood. Here we investigate the immunoglobulin responses of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) to NS1. Antibody responses to recombinant-NS1 are assessed in serum samples throughout illness of patients with acute secondary DENV1 and DENV2 infection by ELISA. NS1 antibody titres are significantly higher in patients with DHF compared to those with DF for both serotypes, during the critical phase of illness. Furthermore, during both acute secondary DENV1 and DENV2 infection, the antibody repertoire of DF and DHF patients is directed towards distinct regions of the NS1 protein. In addition, healthy individuals, with past non-severe dengue infection have a similar antibody repertoire as those with mild acute infection (DF). Therefore, antibodies that target specific NS1 epitopes could predict disease severity and be of potential benefit in aiding vaccine and treatment design.
| S-EPMC6286345 | biostudies-literature
Project description:OBJECTIVE:To characterize the fate of protein and lipid in nascent HDL (high-density lipoprotein) in plasma and explore the role of interaction between nascent HDL and mature HDL in promoting ABCA1 (ATP-binding cassette transporter 1)-dependent cholesterol efflux. Approach and Results: Two discoidal species, nascent HDL produced by RAW264.7 cells expressing ABCA1 (LpA-I [apo AI containing particles formed by incubating ABCA1-expressing cells with apo AI]), and CSL112, human apo AI (apolipoprotein AI) reconstituted with phospholipids, were used for in vitro incubations with human plasma or purified spherical plasma HDL. Fluorescent labeling and biotinylation of HDL were employed to follow the redistribution of cholesterol and apo AI, cholesterol efflux was measured using cholesterol-loaded cells. We show that both nascent LpA-I and CSL112 can rapidly fuse with spherical HDL. Redistribution of the apo AI molecules and cholesterol after particle fusion leads to the formation of (1) enlarged, remodeled, lipid-rich HDL particles carrying lipid and apo AI from LpA-I and (2) lipid-poor apo AI particles carrying apo AI from both discs and spheres. The interaction of discs and spheres led to a greater than additive elevation of ABCA1-dependent cholesterol efflux. CONCLUSIONS:These data demonstrate that although newly formed discs are relatively poor substrates for ABCA1, they can interact with spheres to produce lipid-poor apo AI, a much better substrate for ABCA1. Because the lipid-poor apo AI generated in this interaction can itself become discoid by the action of ABCA1, cycles of cholesterol efflux and disc-sphere fusion may result in net ABCA1-dependent transfer of cholesterol from cells to HDL spheres. This process may be of particular importance in atherosclerotic plaque where cholesterol acceptors may be limiting.
| S-EPMC7176342 | biostudies-literature