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。在共同努力下，世界范围的研究迅速对这种新出现的病毒的生物学和致病性提供了基本的见解。然而，要了解COVID-19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，由于未知原因，从轻度到重度COVID-19疾病的进展与患者的年龄密切相关。严重的COVID-19与早期干扰素反应效率低下，随后免疫反应不足有关。除了危及生命的疾病进展外，SARS-CoV-2感染还可能导致病因不明的严重感染后后遗症。值得注意的是，COVID-19重症和COVID-19后综合征都以多器官表现为特征，并且发生在没有活跃病毒复制的情况下。我们假设SARS-CoV-2诱导受感染细胞表观基因组的变化，并且在感染中存活的表观遗传修饰细胞导致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这种表观遗传改变细胞的积累，并防止破坏性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，可以在体内监测感染细胞的命运。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小鼠，并对以非细胞溶解方式清除病毒的细胞进行表征。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，探索干扰素系统和适应性免疫反应对初始感染细胞存活的作用。最后，我们将研究在非细胞溶解清除SARS-CoV-2后，细胞中仍存在哪些转录组学和表观遗传变化，以及它们对细胞稳态和免疫反应的影响。我们已经成功地建立了一个生理小鼠模型，概括了老年小鼠疾病进展的增强。对于人类来说，这种新的动物模型表明，疾病易感性的增加是由于缺乏及时和协调良好的先天和适应性抗病毒免疫反应，依赖于I型，II型和III型干扰素。此外，用表达Cre重组酶的小鼠适应重组SARS-CoV-2感染我们的Cre报告小鼠，发现在感染后的晚时间点和没有活性病毒复制的情况下，存在大量非细胞溶解清除的细胞。我们独特研究的意义是多方面的。我们希望回答一个紧迫的问题，即在病毒从体内清除后很长一段时间内，感染SARS-CoV-2是否以及如何继续影响细胞稳态和免疫。

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.