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

• DOI: 10.1016/j.isci.2024.109191
• Publication Date: 2024-02-13T17:26:43Z
• Authors: Huabin Zhu; Anuj K. Sharma; Karina Aguilar; Faizan Boghani; Semih Sarcan; Michelle George; Janavi Ramesh; Joshua Van Der Ee...; Chandramukhi S. P...; Aileen Lopez; Wenbo Zhi; Roni Bollag; Nikhil Patel; Kandace Klein; Joe White; Muthusamy Thangaraju; Bal L. Lokeshwar; Nagendra Singh; Vinata B. Lokeshwar
• Keywords: 0301 basic medicine; Biological sciences; Cell biology; 0303 health sciences; Virology; Science; Q; Pathology; Article

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 by C57BL/6 receiving oropharyngeal instillations a ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice COVID-19-like lung pathologies including ground-glass opacities, interstitial fibrosis, congested alveoli, became moribund. Lung tissues from these bronchoalveolar lavage patients showed elevated levels hyaluronic acid (HA), HA-family members, an inflammatory signature, immune cell infiltration. 4-methylumbelliferone (4-MU), oral drug for biliary-spasm treatment, inhibits HA-synthesis. At human equivalent dose, 4-MU prevented/inhibited long-term morbidity; metabolites accumulated lungs. Therefore, versatile pathology, HA as its critical mediator potential therapeutic COVID-19.