Of Mice and MA10

Since the start of the COVID-19 pandemic, scientists have known that SARS-CoV-2 infection can lead to long-term consequences throughout the body, but research into the mechanisms behind lung abnormalities associated with post-acute sequelae of SARS-CoV-2 (PASC) lack longitudinal tissue samples. Mice infected with the mouse-adapted MA10 strain suffer from acute respiratory distress syndrome similar to humans – providing researchers with a prime reference for studying PASC pathogenesis.

Recognizing this, researchers from the University of North Carolina at Chapel Hill extended studies of MA10-infected mice from acute to clinical recovery phases to investigate PASC pathogenesis (1). The mice were autopsied at two, seven, 15, 30, 60, and 120 days post-infection, matching recommendations for diagnosing COVID-19 phases in humans.

By extending the studies to 120 days in one-year-old BALB/c mice, the team demonstrated that many chronic phenotypes seen at 15 days post-infection were also observed for the whole 120-day period – ranging from acute to ongoing to chronic COVID-19 classifications that are also used in humans. Furthermore, fibrotic pulmonary disease peaked at 15 days post-infection in young BALB/c and aged C57BL/6J mice, but waned by 30 days post-infection in many animals compared with aged BALB/c mice. This finding suggests that multiple time points for extended time intervals are needed in future studies of other viral pathogens.

Surviving mice also exhibited higher levels of pro-inflammatory and pro-fibrotic cytokines and, though most returned to normal by the 30-day observation, there was prolonged up-regulation of TGF-β signaling in subpleural fibrotic regions. Early intervention with anti-fibrotic agent nintedanib and antiviral EIDD-2801 modified disease severity and reduced chronic disease, respectively.

The SARS-CoV-2 MA10 mouse model could provide the opportunity for scientists to investigate longitudinal molecular mechanisms behind post-COVID-19 pulmonary disease and monitor the effects of early intervention to improve the long-term consequences of PASC.