Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention
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,
Vinata B. Lokeshwar
Affiliations
Huabin Zhu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Anuj K. Sharma
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Karina Aguilar
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Faizan Boghani
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Semih Sarcan
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Michelle George
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Janavi Ramesh
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Joshua Van Der Eerden
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Chandramukhi S. Panda
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Aileen Lopez
Clinical Trials Office, Augusta University, 1521 Pope Avenue, Augusta, GA 30912, USA
Wenbo Zhi
Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Roni Bollag
Department of Pathology and Biorepository Alliance of Georgia, Medical College of Georgia, Augusta University, 1120 15th St, Augusta, GA 30912, USA; Georgia Cancer Center, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Nikhil Patel
Department of Pathology and Biorepository Alliance of Georgia, Medical College of Georgia, Augusta University, 1120 15th St, Augusta, GA 30912, USA
Kandace Klein
Department of Radiology and Imaging, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA
Joe White
Department of Pathology and Biorepository Alliance of Georgia, Medical College of Georgia, Augusta University, 1120 15th St, Augusta, GA 30912, USA
Muthusamy Thangaraju
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Bal L. Lokeshwar
Georgia Cancer Center, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA
Nagendra Singh
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA; Corresponding author
Vinata B. Lokeshwar
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA; Corresponding author
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.
