Zhu Huabin, Sharma Anuj K, Aguilar Karina, Boghani Faizan, Sarcan Semih, George Michelle, Ramesh Janavi, Van Der Eerden Joshua, Panda Chandramukhi S, Lopez Aileen, Zhi Wenbo, Bollag Roni, Patel Nikhil, Klein Kandace, White Joe, Thangaraju Muthusamy, Lokeshwar Bal L, Singh Nagendra, Lokeshwar Vinata B
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA 30912, USA.
Clinical Trials Office, Augusta University, 1521 Pope Avenue, Augusta, GA 30912, USA.
iScience. 2024 Feb 13;27(3):109191. doi: 10.1016/j.isci.2024.109191. eCollection 2024 Mar 15.
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.
缺乏能够在不要求对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）进行适应性改造的情况下概括新冠肺炎病理的临床前模型，以及人源化/转基因小鼠，这限制了针对频繁出现的关注变异株研发新疗法的研究。我们通过给C57BL/6小鼠经口咽滴注在所有变异株中都常见或特定于德尔塔/奥密克戎变异株的SARS-CoV-2核糖寡核苷酸，并同时给予低剂量博来霉素，开发了无病毒模型。小鼠出现了类似新冠肺炎的肺部病理变化，包括磨玻璃影、间质纤维化、肺泡充血，并濒死。这些小鼠的肺组织以及新冠肺炎患者的支气管肺泡灌洗物和肺组织显示透明质酸（HA）、HA家族成员水平升高，有炎症特征以及免疫细胞浸润。4-甲基伞形酮（4-MU）是一种用于治疗胆道痉挛的口服药物，可抑制HA合成。在人等效剂量下，4-MU预防/抑制了类似新冠肺炎的病理变化和长期发病；4-MU及其代谢产物在小鼠肺中蓄积。因此，这些通用的SARS-CoV-2核糖寡核苷酸经口咽模型概括了新冠肺炎病理，HA是其关键介质，4-MU是新冠肺炎的一种潜在治疗药物。
