Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Laboratory of Molecular and Cellular Immunology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
J Virol. 2018 Jun 13;92(13). doi: 10.1128/JVI.02246-17. Print 2018 Jul 1.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family , SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1 MyD88 mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease. SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.
严重发热伴血小板减少综合征（SFTS）是一种新发传染病，由蜱传白蛉病毒科的 SFTS 病毒（SFTSV）引起。野生型和 I 型干扰素（IFN-I）受体 1 缺陷（IFNAR1）小鼠分别被建立为 SFTSV 感染的非致死性和致死性模型。然而，IFN-I 的产生机制以及导致致死性疾病的因素尚不清楚。通过骨髓嵌合体小鼠，我们发现造血细胞中的 IFN-I 信号对于致死性 SFTSV 感染的存活至关重要。造血细胞中 IFN-I 信号的破坏允许血清中病毒载量增加，并产生过量的多种炎症细胞因子和趋化因子。信号分子 IPS-1 和 MyD88 的缺失消除了 IFN-I 和炎症细胞因子的产生，它们分别是视黄酸诱导基因 I（RIG-I）样受体（RLR）和 Toll 样受体（TLR）信号所必需的。然而，IPS-1MyD88 小鼠对致死性 SFTS 表现出抗性，血清中的病毒载量适中。总之，这些结果表明，在低至中度病毒血症水平下，适当激活 RLR 和 TLR 信号通路有助于通过 SFTSV 感染期间 IFN-I 依赖性抗病毒反应存活，而在高病毒血症水平下这些信号通路的过度激活导致异常诱导多种炎症细胞因子和趋化因子，导致致命疾病。SFTSV 会导致人类发生严重传染病，死亡率高达 12%至 30%。为了了解病毒的发病机制，我们需要阐明先天免疫反应作为抵抗病毒感染的第一道防线。在这里，我们报告称，致死性动物模型表现出由不受控制的先天免疫反应引起的多种炎症细胞因子和趋化因子的异常诱导，从而引发致死性 SFTS。我们的研究结果表明了一种新的策略，即针对炎症体液因子来治疗严重的 SFTS 患者。此外，这项研究可能有助于调查其他蜱传病毒。
