Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection
Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection
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DOI：
10.1172/jci.insight.123158
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发表时间：
2019-02-21
期刊：
影响因子：
8
通讯作者：
Chen, Zhiwei
中科院分区：
文献类型：
--
作者：
Liu, Li;Wei, Qiang;Chen, Zhiwei
新出现的病毒，如严重急性呼吸综合征冠状病毒（SARS-CoV），中东呼吸综合征冠状病毒（MERS-CoV）和H7N9，通过驱动高细胞因子血症和侵袭性炎症通过仍然难以捉摸的机制引起致命的急性肺损伤（ALI）。在SARS-CoV/猕猴模型中，我们确定了在生产性感染的肺中，抗刺突IgG（S-IgG）通过扭曲炎症消退反应引起严重的ALI。肺泡巨噬细胞在急性感染的猕猴中经历了功能极化，同时表现出促炎和伤口愈合的特征。然而，在病毒清除之前S-IgG的存在消除了伤口愈合反应，并促进了MCP 1和IL-8的产生以及促炎性单核细胞/巨噬细胞的募集和积累。重要的是，最终死于SARS的患者（以下称为死亡患者）显示出类似的肺促炎性累积，缺乏伤口愈合巨噬细胞，以及更快的中和抗体应答。他们的血清增强了SARS-CoV诱导的人类单核细胞来源的伤口愈合巨噬细胞产生MCP 1和IL-8，而阻断Fc γ R则降低了这种作用。我们的研究结果揭示了病毒介导的ALI的机制，定义了病毒特异性抗体反应的病理后果，并为治疗SARS-CoV或其他病毒介导的肺损伤提供了潜在的靶点。
Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti-spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV-induced MCP1 and IL-8 production by human monocyte-derived wound-healing macrophages, whereas blockade of Fc gamma R reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury.