1. Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention
- Author
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Huabin Zhu, Anuj K. Sharma, Karina Aguilar, Faizan Boghani, Semih Sarcan, Michelle George, Janavi Ramesh, Joshua Van Der Eerden, Chandramukhi S. Panda, Aileen Lopez, Wenbo Zhi, Roni Bollag, Nikhil Patel, Kandace Klein, Joe White, Muthusamy Thangaraju, Bal L. Lokeshwar, Nagendra Singh, and Vinata B. Lokeshwar
- Subjects
Pathology ,Biological sciences ,Virology ,Cell biology ,Science - Abstract
Summary: The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, and became moribund. Lung tissues from these mice and bronchoalveolar lavage and lung tissues from patients with COVID-19 showed elevated levels of hyaluronic acid (HA), HA-family members, an inflammatory signature, and immune cell infiltration. 4-methylumbelliferone (4-MU), an oral drug for biliary-spasm treatment, inhibits HA-synthesis. At the human equivalent dose, 4-MU prevented/inhibited COVID-19-like pathologies and long-term morbidity; 4-MU and metabolites accumulated in mice lungs. Therefore, these versatile SARS-COV-2 ribo-oligonucleotide oropharyngeal models recapitulate COVID-19 pathology, with HA as its critical mediator and 4-MU as a potential therapeutic for COVID-19.
- Published
- 2024
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