Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV
Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV
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DOI：
10.4049/jimmunol.181.9.6337
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Kohara, Michinori
中科院分区：
文献类型：
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作者：
Yasui, Fumihiko;Kai, Chieko;Kohara, Michinori
严重急性呼吸综合征相关冠状病毒（SARS-CoV）引起严重肺炎的机制细节尚不清楚。我们研究了感染SARS-CoV的BALB/c小鼠在感染SARS-CoV前7-8周皮下接种表达SARS-CoV刺突蛋白（LC16m8rVV-S）或同时表达所有结构蛋白(包括核衣壳(N)、膜(M)、包膜(E)和S蛋白（LC16m8rVV-NNMS）的重组痘苗病毒(W)的免疫反应和病理。lc16m8rvv - nnws免疫组表现出与对照组一样严重的肺炎，尽管LC16m8rVV-NMES与LC16m8rVV-S在相同程度上显著降低了肺部SARS-CoV滴度。为了确定肺炎加重的原因，BALB/c小鼠免疫表达SARS-CoV单个结构蛋白（LC16mOrVV-N, -M, -E, -S）的重组病毒，有或没有LC16mOrVV-S（即LC16mOrVV-N， LC16mOrVV-M, LC16mOrVV-E， LC16mOrVV-S单独或LC16mOrVV-N + LC16mOrVV-S， LC16mOrVV-M + LC16mOrVV-S, LC16mOrVV-E + LC16mOrVV-S），感染SARS-CoV超过4周。LC16mOrVV-N免疫小鼠和LC16mOrVV-N + lc16morvv - s免疫小鼠均表现出严重的肺炎。此外，lc16morvv - n免疫小鼠在感染后表现出Th1 （ifn - γ、IL-2）和Th2 （IL-4、IL-5）细胞因子的显著上调和抗炎细胞因子（IL-10、tgf - β）的下调，导致中性粒细胞、嗜酸性粒细胞和淋巴细胞大量浸润肺，肺泡上皮增厚。这些结果提示，宿主对sars冠状病毒核衣壳蛋白的过度免疫反应参与了sars冠状病毒感染引起的严重肺炎。这些发现增加了我们对SARS发病机制的理解。免疫学杂志，2008,18(1):637 - 648。
The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (W) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NNMS) 7-8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NNWS-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-gamma, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-beta), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS. The Journal of Immunology, 2008, 181: 6337-6348.