Abstract：
Emerging and re-emerging human coronaviruses (hCoVs) cause severe respiratory illness in humans, but the basis for lethal pneumonia in these diseases is not well understood. Alveolar macrophages (AMs) are key orchestrators of host antiviral defense and tissue tolerance during a variety of respiratory infections, and AM dysfunction is associated with severe COVID-19. In this study, using a mouse model of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, we examined the role of AMs in MERS pathogenesis. Our results show that depletion of AMs using clodronate (CL) liposomes significantly increased morbidity and mortality in human dipeptidyl peptidase 4 knock-in (hDPP4-KI) mice. Detailed examination of control and AM-depleted lungs at different days postinfection revealed increased neutrophil activity but a significantly reduced MERS-CoV-specific CD4 T-cell response in AM-deficient lungs during later stages of infection. Furthermore, enhanced MERS severity in AM-depleted mice correlated with lung inflammation and lesions. Collectively, these data demonstrate that AMs are critical for the development of an optimal virus-specific T-cell response and controlling excessive inflammation during MERS-CoV infection.
摘要：
新出现和重新出现的人类冠状病毒（hCoV）会导致人类严重的呼吸道疾病，但是这些疾病中致命性肺炎的基础还不清楚。肺泡巨噬细胞（AMs）是宿主抗病毒防御和组织耐受性在各种呼吸道感染的关键协调，AM功能障碍与严重COVID-19相关。在这项研究中,使用中东呼吸综合征冠状病毒（MERS-CoV）感染的小鼠模型，我们研究了AMs在MERS发病机制中的作用.我们的结果表明，使用氯膦酸盐（CL）脂质体消耗AMs可显着增加人二肽基肽酶4敲入（hDPP4-KI）小鼠的发病率和死亡率。在感染后不同天，对对照和AM耗尽的肺的详细检查显示，中性粒细胞活性增加，但在感染后期，AM缺乏的肺中MERS-CoV特异性CD4T细胞反应显着降低。此外，AM耗竭小鼠的MERS严重程度增强与肺部炎症和病变相关。总的来说，这些数据表明,AMs对于形成最佳病毒特异性T细胞应答和控制MERS-CoV感染期间的过度炎症至关重要.
