登革热病毒抗体依赖增强感染分子机制的体外模型研究-生物化学与分子生物学专业论文.pdf.docxVIP

摘要感染与DENV-ADE感染中自噬程度差异。研究发现，DENV-ADE感染K562细 摘要 感染与DENV-ADE感染中自噬程度差异。研究发现，DENV-ADE感染K562细 胞诱导更高水平的自噬体形成及自噬相关蛋白ATG5，ATGl2表达。通过药物促 进或抑制细胞自噬进程能够剂量依赖性地促进或抑制胞内病毒复制，且完全敲除 自噬相关蛋白ATG5显著抑制胞内病毒复制。结果表明，DENV-ADE感染通过 诱导更强的自噬进而促进胞内病毒增殖。此外，过表达自噬蛋白ATG5能够通过 抑制NF．v．B活化及NOS2表达从而促进病毒增殖。 本研究发现DENV-ADE感染中病毒复制增强是由RIG．I／MDA．5一NF-KB— IRF．1一NOS2固有免疫途径抑制导致的，且该抑制过程不依赖于IL．10--SOCS3 对干扰素途径的抑制。此外DENV-ADE感染能够通过上调细胞自噬进程，抑制 固有免疫途径，从而促进病毒增殖。该研究将有助于加深我们对DENV-ADE感 染机制的理解，并为重症登革患者治疗提供了理论支持和潜在靶点，同时也表明 自噬抑制剂在治疗DENV-ADE引起的重症登革热疾病，以及抑制病毒胞内复制 方面具有潜在的应用价值。 关键词：登革病毒， 抗体依赖性增强感染， I型干扰素， IL．10， 自噬 万方数据 Abs仃actAbstract Abs仃act Abstract Dengue virus(DENV)is mosquito—borne virus causing dramatic public health issues in more than 1 00 countries，particularly in Asia and Latin America，and estimated more than 50 million people infected annually．The geographic expansion of the vector,the Aedesaegypti mosquitoes and Aedes albopictus， contributes to continuous increase in incidence and disease severity． Each of the four serotypes of DENV lead spectrum of outcomes from subclinical to death．Based clinical observations，second heterotypic infection waning immunity of infant born to mother infected by DENV significantly increase the possibility of acquiring disease．Antibody‘dependent enhancement(ADE) has been thought to be involved in the immunopathogenesis of Dengue symptoms like dengue hemorrhagic fever(DHF)and dengue shock syndrome(DSS)· It has been hypothesized that the preexisting heterotypic antibodies form complex with the virus and target cells，via Fc receptors in the target cells，stimulate the infectious properties of virions and facilitate the infection of target cells including monocyte，macrophages and mature DC．Current studies suggested that DENV-ADE infection could suppress IFN—I secretion and function and sequentially promote viral production．Among which IL一1 0 play vital role in DENV-ADE infection through suppressing of IFN signaling．However,the suppression of type I IFN secretion in DENV-ADE infection has