Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium.
Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium.
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流感病毒通过气道上皮中的TLR3增强了睫状活性和粘膜钙的清除。
DOI：
10.1186/s12931-020-01555-1
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发表时间：
2020-10-27
影响因子：
5.8
通讯作者：
Suda T
中科院分区：
文献类型：
--
作者：
Kamiya Y;Fujisawa T;Katsumata M;Yasui H;Suzuki Y;Karayama M;Hozumi H;Furuhashi K;Enomoto N;Nakamura Y;Inui N;Setou M;Ito M;Suzuki T;Ikegami K;Suda T
病毒性呼吸道感染，例如甲型流感病毒 (IAV)，是全世界常见且危及生命的疾病。从呼吸道清除病毒的机制对于呼吸道宿主防御是不可或缺的。粘液纤毛清除是一种气道防御机制，可清除呼吸道中的病原体。气道上皮细胞纤毛跳动的协调和调节在维持有效的粘膜纤毛清除中发挥着关键作用。然而，呼吸道病毒感染对纤毛活动和粘液纤毛清除的影响仍不清楚。气管样本取自野生型 (WT) 和 Toll 样受体 3 (TLR3) 敲除 (KO) 小鼠。在存在或不存在 IAV、polyI:C、合成 TLR3 配体和/或试剂的情况下进行小鼠气管的瞬时器官培养。随后，分析了纤毛驱动的流动和纤毛运动。为了评估纤毛驱动的流动，将红色荧光珠加载到培养基中，并使用荧光显微镜观察珠在气管表面上的运动。为了评估纤毛运动，用用培养基稀释的印度墨水标记纤毛尖端。高速摄像机记录墨水标记的纤毛尖端的运动。与 WT 培养中的对照水平相比，短期 IAV 感染显着增加了纤毛驱动的流量和纤毛跳动频率 (CBF)。然而，在 TLR3-KO 培养物中，IAV 感染不会引起纤毛驱动流量和 CBF 的任何增加，这表明 TLR3 对于响应 IAV 感染引起纤毛驱动流量和 CBF 的增加至关重要。在 WT 培养物中，polyI:C 激活 TLR3 很容易诱导气管中三磷酸腺苷 (ATP) 的释放，并增加纤毛驱动的流量和 CBF，但在 TLR3-KO 培养物中则不然。此外，使用 P2R 拮抗剂苏拉明阻断嘌呤能 P2 受体 (P2R) 信号传导，抑制了 PolyI:C 介导的纤毛驱动流量和 CBF 的增加，表明 TLR3 介导的纤毛激活依赖于释放的细胞外 ATP 和自分泌 ATP-P2R 环。 IAV 感染很容易通过气道上皮中 TLR3 的激活来增加纤毛活动和纤毛驱动的流量，从而加速粘液纤毛清除并从气道中“扫除”病毒，作为最初的宿主防御反应。机械上，响应 TLR3 激活的细胞外 ATP 释放通过自分泌 ATP-P2R 环促进纤毛活动。
Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear. Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras. Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop. IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and “sweeping” viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.
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