CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences , Wuhan, China.
University of Chinese Academy of Sciences , Beijing, China.
J Virol. 2023 Sep 28;97(9):e0079023. doi: 10.1128/jvi.00790-23. Epub 2023 Aug 21.
Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.
蝙蝠携带遗传多样性的严重急性呼吸系统综合征相关冠状病毒(SARSr-CoV)。其中一些利用人类血管紧张素转换酶 2(hACE2)作为受体,并且不能在野生型小鼠中有效复制。我们之前的研究表明,蝙蝠 SARSr-CoV rRsSHC014S 在 hACE2 转基因小鼠中引起呼吸道感染和肺部损伤,但在野生型小鼠中不能。在这项研究中,我们通过在 BALB/c 小鼠中连续传代野生型病毒,生成了一种名为 SMA1901 的 rRsSHC014S 适应小鼠的株系。SMA1901 在小鼠肺部的感染性增加,并在鼻腔接种后引起年轻和老年小鼠的间质性肺炎。基因组测序显示,不仅 Spike 蛋白,而且整个基因组都发生了突变,这可能是 SMA1901 在野生型 BALB/c 小鼠中增强致病性的原因。SMA1901 诱导的与年龄相关的死亡率与 SARS 和 COVID-19 观察到的相似。使用抗体和抗病毒分子进行的药物测试表明,这种适应小鼠的病毒株可用于测试针对 SARSr-CoV 的预防和治疗候选药物。重要性野生动物中 SARSr-CoV 的遗传多样性及其潜在的跨物种感染风险突出了开发强大的动物模型来评估抗体和抗病毒药物的重要性。我们通过在 BALB/c 小鼠中自然连续传代 rRsSHC014S 获得了一种名为 SMA1901 的蝙蝠源性冠状病毒的适应小鼠的株系。SMA1901 感染后通过鼻腔接种,在年轻和老年 BALB/c 小鼠中引起间质性肺炎和炎症免疫反应。我们的模型表现出与 SARS 和 COVID-19 相似的与年龄相关的死亡率。因此,我们的模型对于研究蝙蝠 SARSr-CoV 的发病机制将具有很高的价值,并可作为预防和治疗候选药物的前瞻性测试平台。