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首页> 美国卫生研究院文献>PLoS Pathogens >A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice
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A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice

机译：小鼠适应SARS冠状病毒导致BALB / c小鼠的疾病和死亡。

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No single animal model for severe acute respiratory syndrome (SARS) reproduces all aspects of the human disease. Young inbred mice support SARS-coronavirus (SARS-CoV) replication in the respiratory tract and are available in sufficient numbers for statistical evaluation. They are relatively inexpensive and easily accessible, but their use in SARS research is limited because they do not develop illness following infection. Older (12- to 14-mo-old) BALB/c mice develop clinical illness and pneumonitis, but they can be hard to procure, and immune senescence complicates pathogenesis studies. We adapted the SARS-CoV (Urbani strain) by serial passage in the respiratory tract of young BALB/c mice. Fifteen passages resulted in a virus (MA15) that is lethal for mice following intranasal inoculation. Lethality is preceded by rapid and high titer viral replication in lungs, viremia, and dissemination of virus to extrapulmonary sites accompanied by lymphopenia, neutrophilia, and pathological changes in the lungs. Abundant viral antigen is extensively distributed in bronchial epithelial cells and alveolar pneumocytes, and necrotic cellular debris is present in airways and alveoli, with only mild and focal pneumonitis. These observations suggest that mice infected with MA15 die from an overwhelming viral infection with extensive, virally mediated destruction of pneumocytes and ciliated epithelial cells. The MA15 virus has six coding mutations associated with adaptation and increased virulence; when introduced into a recombinant SARS-CoV, these mutations result in a highly virulent and lethal virus (rMA15), duplicating the phenotype of the biologically derived MA15 virus. Intranasal inoculation with MA15 reproduces many aspects of disease seen in severe human cases of SARS. The availability of the MA15 virus will enhance the use of the mouse model for SARS because infection with MA15 causes morbidity, mortality, and pulmonary pathology. This virus will be of value as a stringent challenge in evaluation of the efficacy of vaccines and antivirals.
机译：严重急性呼吸综合征（SARS）的任何动物模型都无法复制人类疾病的所有方面。年轻的近交小鼠支持SARS冠状病毒（SARS-CoV）在呼吸道中复制，并且有足够的数量用于统计评估。它们相对便宜且易于获得，但由于它们在感染后不会发展成疾病，因此在SARS研究中的使用受到限制。年龄较大（12至14个月大）的BALB / c小鼠会发展为临床疾病和肺炎，但它们可能难以采购，并且免疫衰老使发病机理研究复杂化。我们通过在年轻BALB / c小鼠的呼吸道中进行连续传代来适应SARS-CoV（Urbani株）。十五次传代后产生的病毒（MA15）对鼻内接种的小鼠具有致命性。致死性是在肺中快速和高滴度病毒复制，病毒血症以及病毒传播到肺外部位，并伴有淋巴细胞减少，中性粒细胞增多和肺部病理改变。丰富的病毒抗原广泛分布在支气管上皮细胞和肺泡肺细胞中，并且气道和肺泡中存在坏死性细胞碎片，仅有轻度和局灶性肺炎。这些观察结果表明，感染MA15的小鼠死于压倒性病毒感染，该感染被广泛的，病毒介导的肺细胞和纤毛上皮细胞破坏。 MA15病毒具有6个与适应性和毒力增加相关的编码突变。当引入重组SARS-CoV中时，这些突变会导致高毒力和致死性病毒（rMA15），从而复制了生物学来源的MA15病毒的表型。鼻内接种MA15可重现严重的人类SARS病例中所见疾病的许多方面。 MA15病毒的可用性将增强SARS小鼠模型的使用，因为MA15感染会导致发病率，死亡率和肺部病理。在评估疫苗和抗病毒药的功效时，这种病毒将是严峻的挑战。

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