先天免疫類鐸受體第三型辨識登革病毒之研究

登革病毒是目前重要透過病媒傳播的病毒之一。其臨床表現除了一般典型登革外還可造成嚴重的登革出血熱/登革休克症候群，超過一百個國家曾爆發流行，這些國家最主要位於熱帶和亞熱帶地區。了解登革熱的產生以及登革病毒入侵宿主後與宿主免疫系統的交互作用為疾病預防及治療上重要的課題。人體在登革病毒感染後血液循環中的促發炎細胞激素濃度異常大幅上升的情況被認為是造成嚴重登革出血熱的原因，然而至今對於宿主免疫系統辨識登革病毒進而活化並釋放這些促發炎細胞激素的詳細機制仍不清楚。先前研究顯示，一般病毒感染初期時，免疫系統對病毒的辨識在病程演化上扮演重要角色，其中先天性免疫裡的類鐸受體與病毒的相互作用尤其受到重視。類鐸受體是近年被發現分佈於多種血球細胞上的分子，對於辨識外來致病原並引發局部、全身性發炎反應以及在適應性免疫的引發上佔有重要的角色。本研究著重於探討登革病毒與人類類鐸受體的結合與交互作用，以體外實驗模式觀察類鐸受體在登革病毒感染初期對於細胞激素引發的重要性。本研究結果顯示登革病毒活化人類單核球細胞株需要經由內膜體的酸化作用，顯示細胞膜上的類鐸受體分子無法辨識外來的登革病毒。本實驗進一步利用真核蛋白質表現系統與干擾性核糖核酸技術證實宿主對於登革病毒的辨識主要經由細胞內膜體中的類鐸受體第三型而非細胞膜上的其他受體亞型。除此之外，在體外實驗中亦發現，位於人類腎臟上皮HEK293細胞株中的類鐸受體第三型在偵測登革病毒之後能引發大量的第一型干擾素，進而抑制病毒生長並達到降低細胞病變、提昇細胞存活率的作用。本篇在體外實驗結果說明了登革病毒與人體多種類鐸受體的相互關係，對於登革病毒在登革熱/登革出血熱病人體內引起細胞激素產生的機制也有更進一步的了解。

關鍵字

單核球；巨噬細胞；病毒；細胞激素；細胞活化

並列摘要

Dengue virus (DENV) causes dengue fever (DF) as well as dengue hemorrhagic fever (DHF)/ dengue shock syndrome (DSS) that occur in more than 100 countries and usually in the tropical and subtropical regions of the world. A clearer understanding of its host-virus interaction is imperative for prophylaxis and treatment of this disease. Aberrant cytokine overproduction in host after DENV infection has been established as the cause of DHF. However, the innate immune recognition of DENV and inflammatory response elicited at the initial stages of infection have not been well elucidated. The aim of this study was to clarify the interaction between DENV and human toll-like receptors, which comprise the first line of innate immunity by activating local or systemic inflammatory response. This study found that endosomal acidification is required for DENV-2 to activate the human monocytic cell THP-1. Using the HEK293-TLR expression system and RNAi-based knockdown techniques, the experiments demonstrated that DENV-2 can be recognized mainly by TLR3, but not by the plasma membrane-anchored TLR. Further, TLR3-mediated IFN response has strong potential for inhibiting virus replication and significantly diminishes the in vitro cytopathic effect (CPE) of DENV-2, thus promoting cell survival. The findings of this study illustrate the in vitro interaction between DENV-2 and different TLR molecules which elucidate host-virus interaction and may enhance understanding of viral pathogenesis.

並列關鍵字

Monocytes ； Macrophages ； Viral ； Cytokines ； Chemokines ； Cell Activation

參考文獻

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先天免疫類鐸受體第三型辨識登革病毒之研究

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