Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters.
Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters.
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DOI：
10.1128/jvi.01683-20
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发表时间：
2020-10-27
影响因子：
5.4
通讯作者：
Hooper JW
中科院分区：
文献类型：
--
作者：
Brocato RL;Principe LM;Kim RK;Zeng X;Williams JA;Liu Y;Li R;Smith JM;Golden JW;Gangemi D;Youssef S;Wang Z;Glanville J;Hooper JW
叙利亚仓鼠被用作 SARS-CoV-2 引起的疾病模型。病理学在上呼吸道和下呼吸道中很明显，疾病体征和终点包括体重减轻以及拭子和器官（例如肺）中的病毒RNA和/或传染性病毒。然而，需要高剂量的病毒才能产生疾病，并且疾病会迅速消退。在这里，我们证明免疫抑制的仓鼠容易受到低剂量病毒的影响，并发展出更严重和更持久的疾病。我们使用环磷酰胺瞬时抑制模型证明了新型中和单克隆抗体的功效。此外，我们证明 RAG2 敲除仓鼠在暴露于 SARS-CoV-2 时会患上严重/致命的疾病。这些免疫抑制仓鼠模型为研究人员提供了评估疗法和疫苗以及了解 COVID-19 发病机制的新工具。迫切需要重现人类 COVID-19 疾病（尤其是严重疾病）的动物模型，以了解发病机制并评估候选疫苗和疗法。在这里，我们开发了新型 COVID-19 严重疾病动物模型，涉及叙利亚仓鼠适应性免疫的破坏。环磷酰胺 (CyP) 免疫抑制或 RAG2 敲除 (KO) 仓鼠通过呼吸道途径暴露于严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。 CyP治疗的仓鼠和RAG2 KO仓鼠都出现了比免疫功能正常的仓鼠更严重的临床症状，特别是体重减轻、病毒载量和死亡（仅RAG2 KO）。在短暂免疫抑制的仓鼠中，疾病的时间会延长，在 RAG2 KO 仓鼠中则一致致命。我们评估了中和单克隆抗体的保护功效，发现即使在免疫抑制的动物中，预处理也能限制感染。我们的结果表明，功能性 B 和/或 T 细胞不仅对于清除 SARS-CoV-2 很重要，而且在预防急性疾病方面也发挥着早期作用。重要性 叙利亚仓鼠被用作 SARS-CoV-2 引起的疾病模型。病理学在上呼吸道和下呼吸道中很明显，疾病体征和终点包括体重减轻以及拭子和器官（例如肺）中的病毒RNA和/或传染性病毒。然而，需要高剂量的病毒才能产生疾病，并且疾病会迅速消退。在这里，我们证明免疫抑制的仓鼠容易受到低剂量病毒的影响，并发展出更严重和更持久的疾病。我们使用环磷酰胺瞬时抑制模型证明了新型中和单克隆抗体的功效。此外，我们证明 RAG2 敲除仓鼠在暴露于 SARS-CoV-2 时会患上严重/致命的疾病。这些免疫抑制仓鼠模型为研究人员提供了评估疗法和疫苗以及了解 COVID-19 发病机制的新工具。
Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis. Animal models recapitulating human COVID-19 disease, especially severe disease, are urgently needed to understand pathogenesis and to evaluate candidate vaccines and therapeutics. Here, we develop novel severe-disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than those in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and was uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2 but also play an early role in protection from acute disease. IMPORTANCE Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis.