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

• Applicant: Professor Dr. Martin Schwemmle
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 509483995

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.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Peter Reuther