Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection
Induction of Alternatively Activated Macrophages Enhances Pathogenesis during Severe Acute Respiratory Syndrome Coronavirus Infection
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DOI：
10.1128/jvi.01689-12
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发表时间：
2012-12-01
影响因子：
5.4
通讯作者：
Frieman, Matthew
中科院分区：
文献类型：
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作者：
Page, Carly;Goicochea, Lindsay;Frieman, Matthew
严重急性呼吸综合征冠状病毒（SARS-CoV）感染会导致急性肺损伤（ALI），通常会导致严重的肺部疾病。急性SARS-CoV感染的小鼠模型有助于理解宿主对感染的反应;然而，关于SARS-CoV的发病机制仍有未解之谜。我们的研究表明，STAT 1在SARS-CoV发病机制的严重程度中起着重要作用，并且它在干扰素信号传导中的作用是独立的。缺乏STAT 1的小鼠体重减轻更严重，肺部病变严重，伴有肺纤维化样病变，并且在感染SARS-CoV后免疫反应改变。我们假设STAT 1在免疫反应的极化中起作用，特别是在巨噬细胞中，导致结果恶化。为了测试这一点，我们创建了骨髓嵌合体和细胞类型特异性敲除STAT 1，以确定哪种细胞类型对SARS-CoV感染后预防严重肺部疾病至关重要。骨髓嵌合体实验表明，造血细胞是STAT 1（-/-）小鼠的发病机制，由于诱导的替代激活（AA）巨噬细胞感染后，我们假设，AA巨噬细胞是疾病的严重程度至关重要。建立了单核细胞和巨噬细胞（LysM/STAT 1）或纤毛肺上皮细胞（FoxJ 1/STAT 1）中STAT 1缺失的小鼠。感染后，LysM/STAT 1小鼠显示严重的肺部病理，而FoxJ 1/STAT 1小鼠显示正常的肺部病理。我们假设AA巨噬细胞负责这种STAT 1依赖性病理，因此创建了STAT 1/STAT 6（-/-）双敲除小鼠。STAT 6对AA巨噬细胞的发育至关重要。双基因敲除小鼠的感染显示没有肺部疾病和纤维化前病变，这表明AA巨噬细胞的产生可能是STAT 1依赖性肺部疾病的原因。我们认为STAT 1对AA巨噬细胞的控制对于调节免疫病理和在SARS-CoV感染小鼠模型中防止长期进展为纤维化肺病至关重要。
Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1(-/-) mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6(-/-) double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection.