Dengue NS1 interaction with lipids alters its pathogenic effects on monocyte derived macrophages.

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-09-04 DOI:10.1186/s12929-024-01077-8
Shashika Dayarathna, Bhagya Senadheera, Chandima Jeewandara, Madushika Dissanayake, Farha Bary, Graham S Ogg, Gathsaurie Neelika Malavige
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Abstract

Background: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity.

Methods: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1β levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF.

Results: Significantly higher levels of IL-1β were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1β when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF.

Conclusions: As RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions.

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登革热 NS1 与脂质的相互作用改变了其对单核细胞衍生巨噬细胞的致病作用。
背景:一些研究表明登革热 NS1 抗原与疾病的发病机制有关,但其他研究却没有发现这种联系,原因尚不清楚。急性登革热的 NS1 抗原水平通常与疾病严重程度的增加有关,但根据登革热感染史和感染登革热病毒(DENV)血清型的不同,结果也有很大差异。由于 NS1 与许多宿主脂质相互作用,我们假设 NS1-脂质相互作用的类型会改变其致病性:方法:将原代人类单核细胞衍生巨噬细胞(MDMs)与单独的 NS1 或与高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、LPS 和/或血小板活化因子(PAF)进行共培养,培养基来自有登革热(DF = 8)或登革出血热(DHF = 8)病史的个体。对培养上清液中的 IL-1β 水平进行了测量,并对 MDMs 进行了基因表达分析。单核细胞亚群通过流式细胞术进行评估。使用层次聚类分析和欧氏距离计算来区分聚类。提取了差异表达变量,并建立了一个分类器模型,以区分过去的 DF 和 DHF:结果:NS1与低密度脂蛋白共同培养时,培养上清液中IL-1β的水平显著升高(p = 0.01,中位数 = 45.69 pg/ml),而NS1与高密度脂蛋白共同培养时,IL-1β的水平较低(p = 0.05,中位数 = 4.617 pg/ml)。当 NS1 与 PAF 共同培养时,既往 DHF 患者的 MDM 产生更高水平的 IL-1β (p = 0.02)。当巨噬细胞与单独的 PAF 或与 PAF 结合的 NS1 或与 LDL 结合的 NS1 共同培养时,既往 DHF 患者的 MDM 更有可能下调 RPLP2 基因表达。当NS1与PAF、HDL或LDL共培养时,根据IL10的表达发现了两个集群,但这些集群并不能区分过去的DF或DHF:由于RPLP2在DENV复制、调节细胞应激反应和免疫反应中很重要,而IL-10与严重疾病相关,因此进一步探讨RPLP2和IL-10的不同表达如何在NS1和脂质相互作用的基础上导致疾病的发病机制非常重要。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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