Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention

Area of Science:

• Pathology
• Virology
• Pharmacology

Background:

• Preclinical models for COVID-19 are limited, hindering the development of therapeutics for emerging variants.
• Existing models often require SARS-CoV-2 adaptation or specialized animal strains.

Purpose of the Study:

• To develop versatile, virus-free preclinical models for COVID-19.
• To identify key mediators of COVID-19 pathology and potential therapeutic targets.

Main Methods:

• C57BL/6 mice received oropharyngeal instillation of SARS-CoV-2 ribo-oligonucleotides (common or variant-specific) and low-dose bleomycin.
• Developed lung pathologies were analyzed, including ground-glass opacities and fibrosis.
• Hyaluronic acid (HA) levels, inflammatory markers, and immune cell infiltration were assessed in mouse and human samples.
• The efficacy of 4-methylumbelliferone (4-MU), a hyaluronic acid synthesis inhibitor, was evaluated.

Main Results:

• Mice developed COVID-19-like lung pathologies and morbidity.
• Elevated hyaluronic acid (HA) levels, inflammation, and immune cell infiltration were observed in affected lung tissues.
• 4-methylumbelliferone (4-MU) administration prevented or inhibited COVID-19-like pathologies and long-term morbidity in mice.
• 4-MU and its metabolites were detected in mouse lungs.

Conclusions:

• SARS-CoV-2 ribo-oligonucleotide models effectively recapitulate COVID-19 lung pathology without live virus.
• Hyaluronic acid (HA) is a critical mediator of COVID-19-like pathology in these models.
• 4-methylumbelliferone (4-MU) shows potential as a therapeutic agent for COVID-19.