Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.
Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.
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DOI：
10.1016/j.chom.2016.01.007
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发表时间：
2016-02-10
影响因子：
30.3
通讯作者：
Perlman S
中科院分区：
文献类型：
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作者：
Channappanavar R;Fehr AR;Vijay R;Mack M;Zhao J;Meyerholz DK;Perlman S
高致病性人呼吸道冠状病毒引起急性致死性疾病，其特征在于旺盛的炎症反应和肺损伤。然而，导致肺部病理的因素并不清楚。使用感染SARS（严重急性呼吸道综合征）-CoV的小鼠，我们表明，强大的病毒复制伴随着延迟的I型干扰素（IFN-I）信号转导协调炎症反应和肺免疫病理学与减少生存。IFN-I在病毒滴度达到峰值之前仍可检测到，但早期给予IFN-I可改善免疫病理学。这种延迟的IFN-I信号传导促进致病性炎性单核细胞-巨噬细胞（IMM）的积累，导致肺细胞因子/趋化因子水平升高、血管渗漏和病毒特异性T细胞应答受损。IFN-αβ受体（IFNAR）的基因消融或IMM耗竭可保护小鼠免受致死性感染，而不影响病毒载量。这些结果表明，IFN-I和IMM促进致命的SARS-CoV感染，并确定IFN-I和IMM作为感染病原性冠状病毒和其他呼吸道病毒的患者的潜在治疗靶点。SARS-CoV在BALB/c小鼠中引起致死性呼吸道感染稳健的SARS-CoV复制和延迟的IFN-I信号传导促进疾病IFN-I诱导致病性炎性单核细胞的流入和血管渗漏疾病严重程度在缺乏IFN信号传导的情况下得到改善导致SARS-CoV感染后致死性疾病的因素尚不清楚。Kazappanavar等人显示了强病毒复制和延迟的IFN-I信号传导促进了严重的疾病。IFN-I促进致病性单核细胞-巨噬细胞的积累，导致肺免疫病理学、血管渗漏和次优T细胞应答。
Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses. SARS-CoV causes a lethal respiratory infection in BALB/c mice Robust SARS-CoV replication and delayed IFN-I signaling promote disease IFN-I induces influx of pathogenic inflammatory monocytes and vascular leakage Disease severity is ameliorated in the absence of IFN signaling Factors that lead to lethal disease following SARS-CoV infection are not well understood. Channappanavar et al. show that robust virus replication and delayed IFN-I signaling promote severe disease. IFN-I promotes accumulation of pathogenic monocyte-macrophages resulting in lung immunopathology, vascular leakage, and suboptimal T cell responses.