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

SARS-CoV-2 感染后存活的细胞的重要性

• 批准号: 509483995
• 负责人: Professor Dr. Martin Schwemmle
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Hygiene (IMMH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/509483995?language=en
• 关键词: importance; cells; survive; SARS; CoV

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.

SARS-CoV-2 大流行给人类健康和全球经济带来了重大负担，世界范围内的研究很快就这种新出现的病毒的生物学和致病性提供了基本见解。需要更深入地了解病毒与宿主的相互作用才能了解 COVID-19 并开发有效的治疗方法，例如，由于未知的原因，从轻度到重度 COVID-19 疾病的进展与患者的年龄密切相关。已链接至早期干扰素反应低效，随后免疫反应不足除了危及生命的疾病进展外，SARS-CoV-2 感染还可导致不明原因的严重感染后后遗症，包括严重的 COVID-19 疾病和后遗症。 COVID-19 综合征的特点是多器官表现，并且在没有活跃的病毒复制的情况下发生，我们发现 SARS-CoV-2 会诱导受感染细胞的表观基因组发生变化，并且表观遗传修饰的细胞能够在感染后存活下来。我们进一步提出，早期有效的干扰素反应可以减少这种表观遗传改变细胞的积累，并预防毁灭性的疾病及其长期并发症。我们将用编码 SARS-CoV-2 的小鼠适应 Cre 重组酶感染成年和老年报告小鼠，并表征在小鼠模型中清除病毒的细胞。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 报告小鼠来探索干扰素系统和适应性免疫反应对最初感染细胞存活的作用。将研究 SARS-CoV-2 非细胞溶解清除后细胞中仍保留哪些转录组和表观遗传变化，以及它们对细胞稳态和免疫反应的影响。我们已经成功建立了一个重现疾病进展的生理小鼠模型。正如针对人类的建议，这种新的动物模型表明，疾病易感性增加是由于缺乏及时且良好协调的先天性和适应性抗病毒免疫反应（依赖于 I、II 和 III 型干扰素）所致。我们的 Cre 报告小鼠与表达 Cre 重组酶的小鼠适应性重组 SARS-CoV-2 的研究显示，在感染后的晚期时间点和在没有活性细胞的情况下，存在大量非溶细胞性清除的细胞。我们独特的研究具有多方面的意义，我们希望能够回答这样一个紧迫的问题：在病毒从体内清除后很长一段时间内，SARS-CoV-2 感染是否以及如何继续影响细胞稳态和免疫力。