WEHI Wednesday Seminar hosted by Dr Marcel Doerflinger
 

Stefanie Bader
PhD Student – Doerflinger Laboratory, Infectious Diseases & Immune Defence division – Infection, Inflammation & Immunity Theme, WEHI
(this is a PhD Completion seminar)

Dead or alive? Unveiling the Molecular Mechanisms of SARS-CoV-2 Pathogenesis in vivo

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

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. COVID-19 was a global pandemic of profound complexity, from seemingly asymptomatic cases to severe and life-threatening disease. While the precise mechanisms leading to acute disease are still 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 a higher risk of hospitalization, multiorgan complications and death. Therefore, much still needs to be learned about this complex disease.

Here, 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, even long after the virus is cleared, animals still display pronounced lung inflammation, heart abnormalities and cognitive impairment, collective hallmarks of Long COVID. These models have been critical to study and identify novel vaccines and therapeutics.

Severe COVID-19 is associated with a dysregulated hyperinflammatory immune response. Depending on the cytokine profile, cell death or survival pathways are activated, and these opposing outcomes can lead to inflammation through different mechanisms. Despite the substantial progress in our understanding of COVID-19, which molecular decisions prevail, ultimately causing severe inflammation and death, remain poorly understood. Our existing knowledge of SARS-CoV-2 driven disease 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. Our research sheds light on the molecular decisions occurring during SARS-CoV-2 infection, highlighting the delicate balance between life and death and the difficulty in separating the two.
 

All welcome!