Immune drivers of chronic disease after respiratory viral infections

Respiratory viral infections including SARS-CoV-2 and influenza are the most common infectious illness and are responsible for annual epidemics and occasional pandemics, placing an enormous burden on healthcare systems worldwide. Although typically self-limiting, a variety of host and viral factors determine the extent of lung damage and severity of disease. Tremendous research efforts over the last few decades have led to the advent of effective vaccines, antivirals, and other treatment strategies to mitigate the morbidity and mortality of acute disease. The recent COVID-19 pandemic, however, has further highlighted the potential for respiratory viral infections to lead to the development of chronic post-viral disease in various organ-systems for at least 3 years post-infection. This phenomenon is not unique to SARS-CoV-2 and has been documented after other respiratory viral infections including influenza, SARS-CoV-1, MERS, RSV etc. Despite progress in identifying specific features, we still have limited insight into the underlying pathobiology driving post-viral disease and lack definitive therapeutic interventions to manage this condition. Our study aimed to tackle this by developing animal models recapitulating clinical disease to explore the mechanistic basis of pulmonary sequelae post-infection. Using a combination of human samples and mouse models, we found dysregulated interactions between CD8+ T cells, macrophages and epithelial progenitors within the alveolar space responsible for the development of viral infection-mediated lung fibrosis. We also demonstrated the capacity for therapeutic strategies targeting the immune-system to correct this aberrant immune-epithelial progenitor niche and rescue post-viral lung disease after COVID-19, influenza, and potentially other respiratory viral infections. We further expanded the scope of our study to systemic sequelae in to identify a surprising impact of severe respiratory viral infections on reducing host healthspan and lifespan – a phenomenon described across several clinical cohorts across the globe. Using an animal model, we identified several immune-mediators that remain dysregulated after severe infection to drive the acceleration of age-associated features, resulting in chronic disease and potentially death. We hope that our model will provide a framework to discover therapeutic targets for the millions of individuals at risk of chronic post-viral disease to prevent excess long-term mortality after COVID-19 and potential future viral pandemics.