登革病毒感染經由甘露糖受體與凝集素CLEC5A形成多價異元複合體

Abstract

登革熱是一種好發於全球熱帶與亞熱帶的重要病媒蚊傳染性疾病。登革病毒感染人類巨噬細胞時利用人類甘露糖受體與DC-SIGN作為用以穩定附著於巨噬細胞的主要受體，並利用凝集素CLEC5A作為次要附著受體，用以引發先天免疫系統的訊號傳遞以防禦病毒攻擊。但人類甘露糖受體與DC-SIGN這類主要附著受體如何與凝集素CLEC5A這類訊息受體交互作用與協同功能至今仍沒有被探討。本論文提出一個可能的模型，試著解釋具較強附著能力的受體如甘露糖受體與DC-SIGN與較弱附著能力的受體如CLEC5A，透過共同分布於一個夠小的範圍內以足以與登革熱病毒形成多價異元複合體，高附著能力的受體可以吸引登革病毒穩定在其上，而較弱附著能力的訊息受體可以因為分布在高附著能力受體的周邊提高與登革熱病毒的直接接觸的能力，提高引發先天免疫系統的觸發效率，並以此多價異元複合體賦予病毒附著與訊息傳遞間必要的邏輯連結，且提供抗病毒策略的新穎線索。

Dengue fever is a mosquito-borne viral pandemic disease that is widespread in tropical and subtropical areas. Dengue virus uses human mannose-binding receptor (hMR) and DC-SIGN on macrophages as primary receptors, and CLEC5A as signaling receptor to sense the dengue virus invasion and then to signal and stimulate macrophages to secrete cytokines. But the interplay between hMR/DC-SIGN and CLEC5A is unknown. Here we demonstrate a plausible mechanism for the interaction: hMR/DC-SIGN first attracts the virus with high avidity, then interaction with CLEC5A in close proximity forms a multivalent heterocomplex and facilitates CLEC5A-mediated signal transduction. Our study suggests that the cooperation between a high-avidity lectin-virus interaction and a nearby low-avidity signaling receptor provides a necessary connection between binding and signaling. Understanding this mechanism may lead to the development of a new antiviral strategy.