ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology.
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology.
复制标题
DOI：
10.7554/elife.74623
复制
发表时间：
2022-01-13
期刊：
影响因子：
7.7
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
Gawish R;Starkl P;Pimenov L;Hladik A;Lakovits K;Oberndorfer F;Cronin SJ;Ohradanova-Repic A;Wirnsberger G;Agerer B;Endler L;Capraz T;Perthold JW;Cikes D;Koglgruber R;Hagelkruys A;Montserrat N;Mirazimi A;Boon L;Stockinger H;Bergthaler A;Oostenbrink C;Penninger JM;Knapp S
尽管对新冠肺炎的理解取得了巨大进展，但对免疫学和疾病驱动因素的机械性洞察仍然有限。我们通过人分离株的连续传代获得了小鼠适应的SARS-CoV-2株maVie16。在计算机模拟中揭示了只有三个maVie16尖峰突变如何增强了与小鼠ACE2的相互作用。MaVie16在BALB/c和C57BL/6小鼠中诱导了深刻的病理变化，由此产生的小鼠新冠肺炎(mCOVID-19)复制了人类疾病的关键方面，包括早期淋巴细胞减少、肺免疫细胞浸润、肺炎和特异性适应性免疫。抑制促炎细胞因子干扰素、γ和肿瘤坏死因子可显著降低免疫病理学。重要的是，遗传ACE2缺乏完全阻止了mCOVID-19的发育。最后，重组ACE2的吸入疗法完全保护小鼠免受mCOVID-19的感染，揭示了一种新的有效治疗方法。因此，我们在这里将maVie16作为一种新的工具来对新冠肺炎进行建模，以发现新的治疗方法，并表明疾病的严重程度由细胞因子驱动的免疫病理学决定，并在体内严重依赖血管紧张素转换酶2。
Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.