SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for spillback to New World rodents.
SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for spillback to New World rodents.
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DOI：
10.1371/journal.ppat.1009585
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发表时间：
2021-05
期刊：
影响因子：
6.7
通讯作者：
Schountz T
中科院分区：
文献类型：
--
作者：
Fagre A;Lewis J;Eckley M;Zhan S;Rocha SM;Sexton NR;Burke B;Geiss B;Peersen O;Bass T;Kading R;Rovnak J;Ebel GD;Tjalkens RB;Aboellail T;Schountz T
冠状病毒病-19 （COVID-19）于2019年底在中国出现，并迅速成为大流行。与其他冠状病毒一样，大量证据表明，该病毒起源于马蹄铁蝙蝠（鼻蝠属），可能在扩散到人类之前感染了一个中间宿主。一个重要的担忧是，SARS-CoV-2可能在亚洲以外的二级宿主体内扎根。为了评估这一潜力，我们用SARS-CoV-2攻击鹿小鼠（Peromyscus maniculatus），发现病毒在上呼吸道、肺部和肠道中有很强的复制，在口腔拭子中可检测到病毒RNA长达21天，在肺部可检测到6天。病毒也可能通过味觉-嗅觉-三叉神经通路进入大脑，最终破坏血脑屏障。尽管如此，没有观察到明显的疾病迹象，也没有鹿鼠死于感染。IFNα、IFNβ、Cxcl10、Oas2、Tbk1、Pycard等先天免疫应答基因在肺组织中表达升高。肺中CD4和CD8β表达升高与Tbx21、IFNγ和IL-21表达同时升高，提示存在I型炎症免疫反应。接触传播发生在受感染的幼年鹿小鼠之间，通过两次传代，显示出持续的自然传播和定位到嗅球，再现了人类神经病理学。在鹿鼠的第二次传代中，在刺突蛋白的n端固定区域插入了4个氨基酸，预计会形成一个溶剂可及的环。随后对来自BEI资源的源病毒进行检查，确定该突变存在于非常低的水平，表明在体内传代过程中对插入物进行了有效的纯化选择。总的来说，这项工作已经确定鹿鼠是研究SARS-CoV-2呼吸道疾病和神经发病机制的合适动物模型，并且它们有可能在北美作为二级宿主。一个重要的担忧是，SARS-CoV-2可能在自然野生动物种群中建立，从而导致向人类传播事件。我们已经确定鹿鼠对SARS-CoV-2易感，该病毒可以持续长达21天。此外，还发生了向其他鹿鼠的有效传播，这表明鹿鼠在自然种群中具有持续存在的潜力。在呼吸道观察到的病理与人类COVID-19患者相似，包括强烈的炎症和中性粒细胞和巨噬细胞的浸润，以及嗅球和舌头的神经系统表现，分别可能影响嗅觉和味觉。总的来说，这项工作表明鹿鼠可以作为SARS-CoV-2的二级宿主，也可以作为COVID-19疾病研究的动物模型。
Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNβ, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America. A significant concern is that SARS-CoV-2 could establish in natural wildlife populations that could lead to transmission events to humans. We have determined that deer mice are susceptible to SARS-CoV-2 and that virus can persist for up to 21 days. Moreover, efficient transmission to other deer mice occurred, suggesting the potential for sustained persistence in natural populations of deer mice. The pathology observed in the respiratory tract resembles that which occurs in human COVID-19 patients, including robust inflammation and infiltration of neutrophils and macrophages, and neurological manifestations in the olfactory bulb and tongue that could impact senses of smell and taste, respectively. Collectively, the work suggests deer mice could serve as secondary reservoir hosts of SARS-CoV-2 and as an animal model for COVID-19 disease studies.
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