SPS9-03 Mouse Hepatitis Virus-1 Pneumonia in A/J Mice Provides a Tool to Study the Pathogenesis and Management of SARS-CoV-2, Late-stage Progressive Interstitial Lung Abnormalities

Rationale

Infection with SARS-CoV-2 virus resulted in a subset of patients with progressive interstitial lung abnormalities (ILA) characterized by inflammatory injury and interstitial fibrosis. Understanding mechanisms that drive the development of this ILA may help to predict outcomes and identify targets for early therapeutic intervention. Animal models that simulate the progression of lung injury with SARS-CoV-2 would provide a tool to explore ILA. Mouse hepatitis virus-1 (MHV-1) is a beta-coronavirus which can be studied under biosafetly-level-2 conditions. We have shown that MHV-1 produces a pattern of acute lung injury (ALI) in mice closely simulating SARS-CoV-2 ALI. We have now investigated whether this MHV-1 model is also associated with the development of late-stage ILA similar to SARS-CoV-2.

Methods

A/J mice were challenged with intratracheal MHV-1 or diluent. At 3, 5, 28, 56 or 84d animals were anesthetized for blood measures and then sacrificed for bronchoalveolar lavage (BAL) and lung and liver histology assessment. Up until sacrifice, oxygen saturation and lung function measures with plethysmography were obtained every 3 to 7d. For parameters other than survival, two way analysis of variance examined the overall effect of MHV-1 challenge and the change in the effects of challenge over time.

Results

Pneumonia with MHV-1 produced lethality from 4 to 8d but not later following challenge (Figure). In surviving animals, early ALI evidenced by hypoxemia and increased BAL protein levels were recovering to control levels by 28 to 35d. But not evident until 14d and then persistent for up to 84d following challenge were increased peak and mid-expiratory flow rates and decreased inspiratory pauses suggestive of a developing restrictive pattern of lung function. Consistent with this, on histology, although measures of lung inflammation and alveolar injury were present throughout, lung fibrosis measured with trichrome staining while not present at 3 and 5d, was clearly evident from 28 to 84d.

Conclusion

This MHV-1 beta-coronavirus ALI model is also associated with changes consistent with the development of ILA following infection with SARS-CoV-2 and may be a tool to study the pathogenesis and management of this late-stage condition.

This abstract is funded by: NIH intramural Funds