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

doi:10.1016/j.isci.2024.109191

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

iScience. 2024 Feb 13;27(3):109191. doi: 10.1016/j.isci.2024.109191. eCollection 2024 Mar 15.

Authors

Huabin Zhu¹, Anuj K Sharma¹, Karina Aguilar¹, Faizan Boghani¹, Semih Sarcan¹, Michelle George¹, Janavi Ramesh¹, Joshua Van Der Eerden¹, Chandramukhi S Panda¹, Aileen Lopez², Wenbo Zhi³, Roni Bollag^{4

5}, Nikhil Patel⁴, Kandace Klein⁶, Joe White⁴, Muthusamy Thangaraju¹, Bal L Lokeshwar⁵, Nagendra Singh¹, Vinata B Lokeshwar¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA.
² Clinical Trials Office, Augusta University, 1521 Pope Avenue, Augusta, GA 30912, USA.
³ Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA.
⁴ Department of Pathology and Biorepository Alliance of Georgia, Medical College of Georgia, Augusta University, 1120 15th St, Augusta, GA 30912, USA.
⁵ Georgia Cancer Center, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA.
⁶ Department of Radiology and Imaging, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA.

Abstract

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.

Keywords: Biological sciences; Cell biology; Pathology; Virology.

Grants and funding

R01 CA227277/CA/NCI NIH HHS/United States