Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease
Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease
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DOI：
10.1128/jvi.05957-11
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Baric, Ralph S.
中科院分区：
文献类型：
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作者：
Frieman, Matthew;Yount, Boyd;Baric, Ralph S.
SARS冠状病毒（SARS- cov）引起严重的急性呼吸道疾病，其特征是弥漫性肺泡损伤和透明膜形成。这种病理常发展为人类急性呼吸窘迫（如急性呼吸窘迫综合征[ARDS]）和非典型肺炎，免疫衰老人群的特征性年龄相关死亡率接近50%或更高。sars冠状病毒极端毒力的分子基础仍然难以捉摸。由于幼龄和老年（1岁）小鼠在感染野生型sars冠状病毒后不会出现严重的临床疾病，因此开发了一种小鼠适应的sars冠状病毒毒株（称为MA15），并证明可在这些动物中引起致命感染。为了了解啮齿动物中MA15发病机制增加的遗传因素，我们使用了反向遗传学方法，并评估了编码各种小鼠适应突变组合的衍生病毒组的毒力。我们发现，病毒刺突(S)糖蛋白的突变，以及nsp9非结构蛋白的突变，在较不严格的程度上，主要与幼年动物的毒力获得有关。S的突变可能增加了小鼠血管紧张素转换酶2 （ACE2）受体的识别，不仅在MA15中，而且在另外两种独立分离的小鼠适应sars - cov中也是如此。与幼龄动物的研究结果相反，在12个月大的小鼠中，与其他小鼠适应突变组合相比，nsp9和S糖蛋白恢复到野生型序列的突变不足以显著减弱病毒。这组sars冠状病毒提供了新的试剂，我们已经使用这些试剂来进一步了解人类疾病小鼠模型中与年龄相关的不同致病机制。
SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease.