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Mouse Adapted Omicron BA.5 Induces A Fibrotic Lung Disease Phenotype in BALB/c Mice
John M Powers1, Sarah R Leist1, Naveenchandra Suryadevara2
1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Following SARS-CoV-2 Omicron BA.1, subsequent Omicron sub-lineages have continued to emerge, challenging the development of intervention and prevention strategies, including monoclonal antibodies and vaccines. To better understand the pathogenic effects caused by Omicron BA.5 infection, we developed a mouse-adapted virus with overt disease burden in BALB/c mice. Acute disease was characterized by significant weight loss and lung dysfunction following high-dose challenges. In survivor animals that were followed through 107 days post-infection, subpleural fibrosis with associated tertiary lymphoid structures was noted. Serum from these mice demonstrated potent neutralization against BA.5, with substantially reduced neutralization titers against early epidemic, zoonotic, and more recent contemporary XBB.1.5 variants. Intervention with pre-clinical monoclonal antibodies revealed that robust protection from BA.5-induced lung disease was possible after prophylactic administration. Together, this model enables the investigation of therapeutic approaches for both acute and post-acute sequelae of COVID-19.
Insights
A new mouse model of SARS-CoV-2 Omicron BA.5 infection shows significant lung disease and fibrosis. This model aids in developing treatments for acute and long-term COVID-19 effects.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Emerging SARS-CoV-2 Omicron sub-lineages, like BA.5, pose challenges to existing vaccines and therapeutics.
- Understanding the pathogenicity of Omicron variants is crucial for effective control strategies.
Purpose of the Study:
- To develop and characterize a mouse-adapted model for Omicron BA.5 infection.
- To investigate the acute and post-acute pathological effects of BA.5 in a mammalian model.
- To evaluate the efficacy of therapeutic interventions against BA.5 infection.
Main Methods:
- Development of a mouse-adapted SARS-CoV-2 Omicron BA.5 strain.
- High-dose intranasal challenge in BALB/c mice to assess disease burden.
- Longitudinal monitoring of infected mice for pathological changes and immune responses.
- In vitro neutralization assays and in vivo efficacy studies with monoclonal antibodies.
Main Results:
- Mouse-adapted BA.5 caused significant weight loss and lung dysfunction in BALB/c mice.
- Survivors developed subpleural fibrosis and tertiary lymphoid structures.
- Mouse serum neutralized BA.5 but showed reduced activity against other variants (e.g., XBB.1.5).
- Prophylactic monoclonal antibody treatment protected against BA.5-induced lung disease.
Conclusions:
- The developed mouse model recapitulates key features of severe Omicron BA.5 infection.
- This model is valuable for studying both acute disease and long-term sequelae of COVID-19.
- Therapeutic strategies, including monoclonal antibodies, show promise for mitigating BA.5-related pathology.
