SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.

中文翻译：

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人类恢复期血浆保护 K18-hACE2 小鼠免受严重呼吸道疾病

SARS-CoV-2 是 COVID-19 的病原体，人类感染已导致全球卫生紧急情况。需要重现 SARS-CoV-2 人类感染关键要素的小动物模型来严格筛选候选药物，以减轻严重疾病并防止 SARS-CoV-2 的传播。我们和其他人报道，在角蛋白 18 (K18) 启动子控制下表达人血管紧张素转换酶 2 (hACE2) 病毒受体的转基因小鼠在 SARS-CoV-2 鼻内攻击后出现严重且致命的呼吸道疾病。在这里，我们报告说，尽管存在抗 SARS-COV-2 中和抗体，但一些在攻击后幸存下来的受感染小鼠在感染后第 28 天仍存在残余肺部损伤和持续性脑部感染。由于 K18-hACE2 小鼠对 SARS-CoV-2 过敏以及病毒感染大脑的倾向，我们试图确定抗感染生物制剂是否可以在该模型系统中预防疾病。我们证明抗 SARS-CoV-2 人类恢复期血浆可以保护 K18-hACE2 免受严重疾病的侵害。所有对照小鼠均在第 7 天死于疾病；然而，所有接受治疗的小鼠都在感染后存活下来，并且没有观察到疾病迹象。与对照小鼠形成鲜明对比的是，抗体治疗小鼠的肺部病毒抗原和病变减少或不存在，而大脑中也不存在。我们的研究结果支持使用 K18-hACE2 小鼠进行抗 SARS-CoV-2 医疗对策 (MCM) 的保护功效研究。他们还支持使用该系统来研究 SARS-CoV-2 持久性和宿主恢复。