血清内皮和炎症生物标志物在确定登革热感染患者疾病严重程度方面的诊断和治疗潜力的意义。
Significance of diagnostic and therapeutic potential of serum endothelial and inflammatory biomarkers in defining disease severity of dengue infected patients.
作者信息
Ghosh Priyanka, Saha Bibhuti, Kaveri Krishnasamy, Tripathi Anusri
机构信息
Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073, West Bengal, India.
Department of Tropical Medicine, Infectious Diseases and Advanced Microbiology, Calcutta School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073, West Bengal, India.
出版信息
Med Microbiol Immunol. 2024 Dec 14;214(1):3. doi: 10.1007/s00430-024-00810-2.
Dengue virus (DENV) mediated disease severity leads to fatality among infected patients. Immune sentinels recognize DENV thereby secreting inflammatory mediators, endothelial biomarkers and anticoagulation factors. Absence of any diagnostic biomarkers for early identification of severe dengue (SD) patients has hindered disease management. Present study is aimed to evaluate diagnostic potential of these biomarkers along with their therapeutic targets for disease severity. Dengue infection was screened among 214 symptomatic patients and 25 healthy individuals by qRT-PCR, NS1-antigen, anti-dengue-IgM, anti-dengue-IgG ELISA and categorized them according to WHO-classification, 2009. Dengue viral-load and serotypes were determined by qRT-PCR. Serum-protein concentrations of inflammatory mediators (MIF, PAF, MMP2, MMP9, MCP1, RANTES, STNFRI, ST2, EOTAXIN), endothelial biomarkers (SDC1, VEGF, ANGPT2), anticoagulation factors (sTM, vWF, TF, PAI) were determined by sandwich ELISA. Statistical, PPI-network, hub-proteins, drug prediction analysis were performed by GraphPad-Prism, STRING, Cytoscape-cytoHubba, DrugBank online, TTD, respectively. Among 81 dengue infected patients, significantly higher levels of MIF, PAF, sTNFRI, MMP9, VEGF, ANGPT2, MMP2, RANTES, SDC1 were detected among SD patients compared to non-severe ones, with excellent and good diagnostic potential of first (> 77.11, > 57.57 ng/ml, > 3226 pg/ml) and next three (> 105.3 ng/ml, > 12,380, > 8284 pg/ml) biomarkers, respectively. Serum MIF, PAF, MMP9, sTNFRI levels were significantly higher among hospitalized (p-value: 0.0081-0.0499), high-viral-load (p-value: 0.0266-0.0466) and DENV-2, 4 (p-value: < 0.0001-0.0298) infected patients. PPI-network analysed MMP9, PAI, vWF, ANGPT2, sTM, sTNFRI, MIF as hub-proteins targeted by FDA-approved/experimental drugs. This study recognized serum-biomarkers: MIF, PAF, sTNFRI, MMP9, VEGF, ANGPT2 to have significant diagnostic potential for identification of SD cases.
登革病毒（DENV）介导的疾病严重程度会导致感染患者死亡。免疫哨兵识别DENV，从而分泌炎症介质、内皮生物标志物和抗凝因子。缺乏用于早期识别重症登革热（SD）患者的诊断生物标志物阻碍了疾病管理。本研究旨在评估这些生物标志物的诊断潜力及其针对疾病严重程度的治疗靶点。通过定量逆转录聚合酶链反应（qRT-PCR）、NS1抗原、抗登革热IgM、抗登革热IgG酶联免疫吸附测定（ELISA）在214例有症状患者和25名健康个体中筛查登革热感染，并根据2009年世界卫生组织分类对他们进行分类。通过qRT-PCR确定登革病毒载量和血清型。通过夹心ELISA测定炎症介质（巨噬细胞移动抑制因子（MIF）、血小板活化因子（PAF）、基质金属蛋白酶2（MMP2）、基质金属蛋白酶9（MMP9）、单核细胞趋化蛋白1（MCP1）、调节激活正常T细胞表达和分泌因子（RANTES）、可溶性肿瘤坏死因子受体I（sTNFRI）、白介素1受体拮抗剂（ST2）、嗜酸性粒细胞趋化因子（EOTAXIN））、内皮生物标志物（ Syndecan-1（SDC1）、血管内皮生长因子（VEGF）、血管生成素2（ANGPT2））、抗凝因子（可溶性血栓调节蛋白（sTM）、血管性血友病因子（vWF）、组织因子（TF）、纤溶酶原激活物抑制剂（PAI））的血清蛋白浓度。分别通过GraphPad Prism、STRING、Cytoscape-cytoHubba、DrugBank在线数据库、治疗靶点数据库（TTD）进行统计分析、蛋白质-蛋白质相互作用（PPI）网络分析、枢纽蛋白分析和药物预测分析。在81例登革热感染患者中，与非重症患者相比，SD患者中检测到的MIF、PAF、sTNFRI、MMP9、VEGF、ANGPT2、MMP2、RANTES、SDC1水平显著更高，前三种生物标志物（分别>77.11、>57.57 ng/ml、>3226 pg/ml）和接下来三种生物标志物（分别>105.3 ng/ml、>12380、>8284 pg/ml）具有优异和良好的诊断潜力。住院患者（p值：0.0081 - 0.0499）、高病毒载量患者（p值：0.0266 - 0.0466）以及感染DENV-2、4型病毒的患者（p值：<0.0001 - 0.0298）血清中MIF、PAF、MMP9、sTNFRI水平显著更高。PPI网络分析显示MMP9、PAI、vWF、ANGPT2、sTM、sTNFRI、MIF为枢纽蛋白，有美国食品药品监督管理局（FDA）批准的/实验性药物作为靶点。本研究确认血清生物标志物MIF、PAF、sTNFRI、MMP9、VEGF、ANGPT2对识别SD病例具有显著诊断潜力。
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