During the course from pandemic to endemic, SARS-CoV-2 transformed our lives in many ways. However, this persistent yet not entirely novel coronavirus still has surprises up its sleeve. While the precise mechanisms leading to acute disease are not fully understood, the cumulative damage of infection is now giving rise to a second pandemic of its long-term effects. Regardless of vaccination status, a resolved infection correlates with higher risk of hospitalization, multiorgan complications and death. Therefore, much still needs to be learned about this complex disease.
We developed unique pre-clinical in vivo models that reproduce aspects of mild, severe and fatal COVID-19. By serially passaging a clinical SARS-CoV-2 isolate in mice, we generated a mouse adapted strain that causes weight loss, inflammation and lung pathology in adult mice and is deadly in aged animals, reflecting key aspects of human disease. Interestingly, months after the virus is cleared, animals still display pronounced lung inflammation, heart abnormalities and cognitive impairment, collective hallmarks of Long COVID.
COVID-19 and its long-term sequelae have been associated with a dysregulated hyperinflammatory immune response. Depending on the cytokine profile, cell dead or survival pathways are activated, and these opposing outcomes can both lead to inflammation. Our existing knowledge of SARS-CoV-2 predominantly relies on correlative or in vitro studies, and it is yet unclear which pathways are causative of severe inflammation in vivo. Here, we utilise our pre-clinical models to conduct a detailed gene-targeted investigation to understand and systematically dissect the pathways underlying SARS-CoV-2 pathogenesis.
Using proteomic, transcriptomic and genetic approaches, we show that TNF and IL-1b drive pathogenesis. Interestingly, inflammasome pathways upstream of canonical IL-1b release do not influence disease outcomes in vivo. Similarly, the lytic process of necroptosis, which lies downstream of TNF, does not contribute to SARS-CoV-2 driven disease. Instead, the central determinant of severe disease outcome is Caspase-8, a protein essential for the activation of apoptosis. Remarkably, instead of triggering cell death, SARS-CoV-2 infection drives Caspase-8 to activate survival/inflammatory pathways. In this study, we shed light on the molecular decisions that Caspase-8 makes in response to SARS-CoV-2: the fine balance between inflammation and cell death.