TY - JOUR
T1 - Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention
AU - Zhu, Huabin
AU - Sharma, Anuj K.
AU - Aguilar, Karina
AU - Boghani, Faizan
AU - Sarcan, Semih
AU - George, Michelle
AU - Ramesh, Janavi
AU - Van Der Eerden, Joshua
AU - Panda, Chandramukhi S.
AU - Lopez, Aileen
AU - Zhi, Wenbo
AU - Bollag, Roni
AU - Patel, Nikhil
AU - Klein, Kandace
AU - White, Joe
AU - Thangaraju, Muthusamy
AU - Lokeshwar, Bal L.
AU - Singh, Nagendra
AU - Lokeshwar, Vinata B.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/3/15
Y1 - 2024/3/15
N2 - 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.
AB - 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.
KW - Biological sciences
KW - Cell biology
KW - Pathology
KW - Virology
UR - http://www.scopus.com/inward/record.url?scp=85185803390&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85185803390&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.109191
DO - 10.1016/j.isci.2024.109191
M3 - Article
AN - SCOPUS:85185803390
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 3
M1 - 109191
ER -