玻尿酸對於重症登革熱病人徵象預測及治療應用
玻尿酸對於重症登革熱病人徵象預測及治療應用
嚴重登革熱感染的主要病理特徵是血管內皮細胞通透性過度升高，進而增加血漿滲漏形成紅色皮疹症狀，但其所涉及的分子機制尚不清楚。在本研究中我們追踪了250名登革熱患者，記錄了患者血清玻尿酸濃度和其他的臨床參數與玻尿酸受體CD44蛋白質表現量。結果發現登革熱病程早期患者之血清玻尿酸濃度升高（>70 ng/ml），可以當作警示徵象和發生嚴重登革熱的預測因子。另外，血液中登革病毒NS1蛋白質濃度與血液中登革病毒NS1蛋白質濃度與血清玻尿酸程度呈現高度相關。 NS1蛋白質可以降低血管內皮細胞CD44受體的表現，損害了血管構造的完整性，並且與登革病毒誘發的促進發炎物質協同作用，增進了皮膚纖維母細胞和血管內皮細胞中玻尿酸的合成。在體外培養的細胞周圍可發現含有玻尿酸的細胞外基質，這暗示了血管內皮細胞中玻尿酸與CD44受體的交互作用被干擾，並且藉由調節VE-cadherin依賴性黏著分子蛋白和細胞骨架的重新組織來增加血管內皮細胞滲漏性。血液中過多的玻尿酸分子則會加重了登革熱NS1蛋白質誘發的血管內皮細胞受破壞的情形。
圖形摘要
【應用與亮點】
探討玻尿酸及其結合蛋白與裂解酶之交互作用，在登革病毒感染症的病生理角色，並以動物模式及臨床試驗評估調控玻尿酸藥物的療效
【研究團隊】
團隊成員：陳彥旭、林俊祐、王文宏
代表單位：熱帶醫學暨傳染病研究中心
團隊簡介：熱帶醫學暨傳染病研究中心團隊在疫苗、藥物及試劑等研發領域，建立產官學與國際合作關係，推動熱帶疾病與傳染病之治療、檢驗及疫苗與藥物臨床試驗。
研究聯繫Email：infchen@gmail.com; infectionman@gmail.com
【論文資訊】
論文出處：EBioMedicine., 2019 Oct; 48:425-441
全文下載：https://pubmed.ncbi.nlm.nih.gov/31526718/
Serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity
Serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity
A main pathological feature of severe dengue virus infection is endothelial hyperpermeability. However, the molecular mechanisms involved in dengue induced hyperpermeability are still unclear. In this study, a cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Serum hyaluronan levels and several other clinical parameters were recorded including the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44 expression level. The result shows that the elevated serum hyaluronan levels (>70ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 treatment could decrease the expression of CD44 in endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. The hyaluronan-CD44 interaction enhance endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1- induced disruption of endothelial integrity.
Graphical Abstract
Schematic illustration of a possible mechanism for NS1-induced increased endothelium permeability. (a) Under physiological conditions, balanced expression of CD44 and hyaluronan levels contribute to cell-to-cell adhesion by cross-bridging between cells and maintaince of an intact glycocalyx. (b) During severe dengue virus infection, the excessive levels of partly fragmented hyaluronan occupy the reduced number of CD44 receptors, thus preventing efficient cross-bridging. In addition, disruption of the glycocalyx layer may contribute to increased permeability.
Research Team Members: Yen-Hsu Chen, Chun-Yu Lin, Wen-Hung Wang
Representative Department: Center for Tropical Medicine and Infection disease
Introduction of Research Team:
The team of the Tropical Medicine and Infectious Disease Research Center has established industry-government-academia and international cooperation in the fields of vaccine, drug and reagent research and development. We also promote the treatment and clinical trials of vaccines and drugs for tropical diseases and infectious diseases.
Contact Email: infchen@gmail.com; infectionman@gmail.com
Publication: EBioMedicine., 2019 Oct; 48:425-441
Full-Text Article: https://pubmed.ncbi.nlm.nih.gov/31526718/
