Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity.
Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity.
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DOI：
10.1038/srep17577
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发表时间：
2015-12-02
影响因子：
4.6
通讯作者：
Hara H
中科院分区：
文献类型：
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作者：
Uematsu T;Iizasa E;Kobayashi N;Yoshida H;Hara H
流感病毒（Influenza virus，IFV）感染是导致重症病毒性肺炎（severe viral pneumonia）合并急性呼吸窘迫综合征（acute respiratory distress syndrome，ARDS）的常见原因，由于其对病毒复制的不利影响，包括糖皮质激素在内的常规免疫抑制治疗难以控制。研究表明，IFV对先天免疫的过度激活是导致严重病理的原因。在这项研究中，我们专注于CARD 9，一种已知通过多种先天传感器蛋白调节先天免疫激活的信号适配器，并研究了其在小鼠模型中的抗IFV防御和肺部发病机制中的作用，该模型重现了严重流感肺炎伴ARDS。我们发现，流感肺炎在Card 9缺陷小鼠中显著减弱，这表明死亡率提高，感染肺部的炎性细胞因子和趋化因子减少。然而，病毒清除、I型干扰素产生以及抗病毒B和T细胞免疫的发展并不受CARD 9缺陷的影响。Syk或CARD 9缺陷型DC而不是巨噬细胞在体外对IFV的反应中显示出受损的细胞因子而不是I型干扰素产生，表明Syk-CARD 9通路在DC中在IFV感染的肺的过度炎症中可能起作用。因此，抑制该途径是重症流感肺炎的理想治疗靶点，而不影响病毒清除。
Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.