Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS-CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV-2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

中文翻译：

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STAT2信号转导为双刃剑，限制了病毒的传播，但在SARS-CoV-2感染的仓鼠中引发了严重的肺炎

自从出现导致COVID-19的SARS-CoV-2以来，无数次的住院治疗和数十万的死亡使世界陷入了震撼。为了寻找有效疗法的关键目标，迫切需要模仿人类COVID-19的健壮动物模型。在这里，我们表明小鼠肺中生产性SARS-CoV-2感染受到早期I型干扰素反应的限制和限制。相反，我们表明叙利亚仓鼠高度允许SARS-CoV-2并在中性粒细胞浸润和水肿的肺部形成支气管肺炎和强烈的炎症反应。此外，我们发现旺盛的先天免疫应答是发病机理中的关键角色，其中STAT2信号传导起双重作用，一方面导致严重的肺损伤，另一方面又限制了系统性病毒的传播。最后，我们通过临床实践中使用的微型CT评估了SARS-CoV-2诱导的仓鼠肺部病理。我们的结果揭示了依赖STAT2的干扰素应答在SARS-CoV-2感染期间的发病机制和病毒控制中的重要性，并且可能有助于合理化治疗COVID-19患者的新策略。