The importance of cells which survive SARS-CoV-2 infection

SARS-CoV-2大流行给人类健康和全球经济带来了重大负担。通过共同努力，世界范围内的研究迅速提供了对这种新出现的病毒的生物学和致病性的基本见解。然而，要理解新冠肺炎并开发有效的治疗方法，需要更深入地了解病毒与宿主的相互作用。例如，新冠肺炎病从轻度到重度的进展与患者的年龄密切相关，原因不明。严重的新冠肺炎早期被认为与干扰素反应低效有关，随后是免疫反应不足。除了危及生命的疾病进展外，SARS-CoV-2感染还可能导致原因不明的严重感染后后遗症。值得注意的是，严重的新冠肺炎病和后新冠肺炎综合征都以多器官症状为特征，并在没有活跃的病毒复制的情况下发生。我们假设SARS-CoV-2引起感染细胞表观基因组的变化，在感染中存活下来的表观遗传修饰细胞有助于严重的疾病进展和长期后遗症。我们进一步提出，早期和有效的干扰素反应减少了这种表观遗传改变细胞的积累，防止了毁灭性的疾病及其长期并发症。我们已经建立了一个Cre报告小鼠模型，可以监测体内受感染细胞的命运。我们将用小鼠适应的编码SARS-CoV-2的Cre重组酶感染成年和老年报告鼠，并鉴定以非细胞溶解方式清除病毒的细胞。此外，我们将通过使用缺乏干扰素受体或缺乏适应性免疫系统的Cre报告小鼠，探索干扰素系统和获得性免疫反应对初始感染细胞存活的作用。最后，我们将研究SARS-CoV-2在非细胞溶解清除后，细胞中仍然存在哪些转录和表观遗传变化，以及它们对细胞动态平衡和免疫反应的影响。我们已经成功地建立了一个生理性的小鼠模型，概括了老年小鼠疾病进展的加速。正如对人类的建议，这个新的动物模型表明，疾病易感性的增加是由于缺乏及时和良好协调的先天和适应性抗病毒免疫反应，依赖于I、II和III型干扰素。此外，用表达Cre重组酶的小鼠适应的重组SARS-CoV-2感染我们的Cre报告小鼠，发现在感染后的后期时间点存在大量非细胞清除的细胞，并且在没有活跃的病毒复制的情况下。我们独特研究的意义是多方面的。我们期待着回答一个紧迫的问题，即感染SARS-CoV-2是否以及如何在病毒从体内清除很长时间后继续影响细胞的动态平衡和免疫。

The SARS-CoV-2 pandemic imposes a major burden on human health, as well as the global economy. In a joint endeavor, world-wide research has quickly provided fundamental insights into the biology and pathogenicity of this newly emerging virus. Yet, a deeper understanding of the virus-host interactions is required to understand COVID-19 and to allow the development of effective treatments. For example, progression from mild to severe COVID-19 disease correlates strongly with the patient’s age for unknown reasons. Severe COVID-19 has been linked to an inefficient interferon response early on, followed by an insufficient immune response. In addition to life-threatening disease progression, SARS-CoV-2 infections can lead to severe postinfectious sequelae of unknown etiology. Strikingly, both severe COVID-19 disease and the post-COVID-19 syndrome are characterized by multi-organ manifestations and occur in the absence of active viral replication. We hypothesize that SARS-CoV-2 induces changes in the epigenome of infected cells and that epigenetically modified cells that survive the infection contribute to severe disease progression and long-term sequelae. We further propose that an early and efficient interferon response diminishes the accumulation of such epigenetically altered cells and prevents devastating disease, as well as its long-term complications. We have established a Cre-reporter mouse model that allows to monitor the fate of infected cells in vivo. We will infect both adult and aged reporter mice with a mouse-adapted Cre recombinase-encoding SARS-CoV-2 and characterize cells that cleared the virus in a non-cytolytic manner. Furthermore, we will explore the role of both the interferon system and the adaptive immune response for the survival of initially infected cells, by using Cre-reporter mice devoid of interferon receptors or lacking an adaptive immune system. Finally, we will study which transcriptomic and epigenetic changes remain in cells after non-cytolytic clearance of SARS-CoV-2 and what their impact is on cellular homeostasis and immune responses. We already succeeded to establish a physiological mouse model recapitulating enhanced disease progression in aged mice. As suggested for humans, this novel animal model indicates that increased disease susceptibility is driven by the lack of a timely and well-coordinated innate and adaptive antiviral immune response, relying on type I, II and III interferons. Furthermore, infection of our Cre-reporter mice with a mouse-adapted recombinant SARS-CoV-2 expressing the Cre recombinase revealed the presence of numerous non-cytolytically cleared cells at late time points after infection and in the absence of active viral replication. The implications of our unique research are manifold. We expect to answer the urgent question whether and how an infection with SARS-CoV-2 continues to affect cellular homeostasis and immunity long after the virus has been cleared from the body.