Sprokholt Joris K, Kaptein Tanja M, van Hamme John L, Overmars Ronald J, Gringhuis Sonja I, Geijtenbeek Teunis B H
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands.
J Immunol. 2017 Jun 15;198(12):4764-4771. doi: 10.4049/jimmunol.1602121. Epub 2017 May 15.
Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses. DENV infection induced DC maturation and secretion of IL-1β, IL-6, and TNF. Inhibition of DENV RNA replication abrogated these responses. Notably, silencing of RNA sensors RIG-I or MDA5 abrogated DC maturation, as well as cytokine responses by DENV-infected DCs. DC maturation was induced by type I IFN responses because inhibition of IFN-α/β receptor signaling abrogated DENV-induced DC maturation. Moreover, DENV infection of DCs resulted in CCL2, CCL3, and CCL4 expression, which was abrogated after RIG-I and MDA5 silencing. DCs play an essential role in T cell differentiation, and we show that RIG-I and MDA5 triggering by DENV leads to T1 polarization, which is characterized by high levels of IFN-γ. Notably, cytokines IL-6, TNF, and IFN-γ and chemokines CCL2, CCL3, and CCL4 have been associated with disease severity, endothelial dysfunction, and vasodilation. Therefore, we identified RIG-I and MDA5 as critical players in innate and adaptive immune responses against DENV, and targeting these receptors has the potential to decrease hemorrhagic fever in patients.
登革病毒（DENV）每年导致4亿人感染，是几种可引起病毒性出血热的病毒之一，其特征是不受控制的免疫激活，导致高热和内出血。尽管其潜在机制尚不清楚，但大量细胞因子分泌被认为与之有关。树突状细胞（DC）是DENV的主要靶细胞，我们研究了它们在DENV诱导的细胞因子产生和适应性免疫反应中的作用。DENV感染诱导DC成熟并分泌IL-1β、IL-6和TNF。抑制DENV RNA复制可消除这些反应。值得注意的是，RNA传感器RIG-I或MDA5的沉默消除了DC成熟以及DENV感染的DC的细胞因子反应。DC成熟是由I型干扰素反应诱导的，因为抑制IFN-α/β受体信号传导可消除DENV诱导的DC成熟。此外，DENV感染DC导致CCL2、CCL3和CCL4表达，在RIG-I和MDA5沉默后这种表达被消除。DC在T细胞分化中起重要作用，我们表明DENV触发RIG-I和MDA5导致T1极化，其特征是高水平的IFN-γ。值得注意的是，细胞因子IL-6、TNF和IFN-γ以及趋化因子CCL2、CCL3和CCL4与疾病严重程度、内皮功能障碍和血管舒张有关。因此，我们确定RIG-I和MDA5是针对DENV的先天性和适应性免疫反应中的关键参与者，靶向这些受体有可能降低患者的出血热发病率。
