Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+ T Cells Are Important in Control of SARS-CoV Infection
Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+ T Cells Are Important in Control of SARS-CoV Infection
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DOI：
10.1128/jvi.01281-09
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发表时间：
2010-02-01
影响因子：
5.4
通讯作者：
Subbarao, Kanta
中科院分区：
文献类型：
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作者：
Chen, Jun;Lau, Yuk Fai;Subbarao, Kanta
我们描述了12至14个月大的BALB/c小鼠对严重急性呼吸综合征冠状病毒（SARS-CoV）感染的细胞免疫反应，这是一种模仿人类疾病特征的模型。经鼻给药后，病毒在肺部复制，在感染后第2天滴度达到峰值。细胞因子（肿瘤坏死因子α [tnf - α]和白细胞介素-6 [IL-6]）和趋化因子（CXCL10、CCL2、CCL3和CCL5）的增加与NK细胞、巨噬细胞和浆细胞样树突状细胞（pDC）向肺部迁移相关。到第7天，当病毒清除发生时，肺部出现肺炎的组织病理学证据。此时，在肺部检测到第二波细胞因子（tnf - α、IL-6、γ干扰素[ifn - γ]、IL-2和IL-5）、趋化因子（CXCL9、CXCL10、CCL2、CCL3和CCL5）和受体（CXCR3、CCR2和CCR5）的增强产生，与T淋巴细胞的涌入有关。感染时CD8(+) T细胞的耗竭不影响病毒复制或清除。然而，CD4(+) T细胞的耗竭导致免疫介导的间质性肺炎增强和sars冠状病毒从肺部的清除延迟，这与中和抗体和细胞因子产生减少以及肺淋巴细胞募集减少有关。先天防御机制能够在缺乏CD4（+）和CD8(+) T细胞和抗体的情况下控制SARS-CoV感染。我们的研究结果为SARS的发病机制提供了新的见解，证明了CD4(+) T细胞而不是CD8(+) T细胞在该模型中原发性SARS- cov感染中的重要作用。
We characterized the cellular immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 12- to 14-month-old BALB/c mice, a model that mimics features of the human disease. Following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. Enhanced production of cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) correlated with migration of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of cytokines (TNF-alpha, IL-6, gamma interferon [IFN-gamma], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. Depletion of CD8(+) T cells at the time of infection did not affect viral replication or clearance. However, depletion of CD4(+) T cells resulted in an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs, which was associated with reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of lymphocytes. Innate defense mechanisms are able to control SARS-CoV infection in the absence of CD4(+) and CD8(+) T cells and antibodies. Our findings provide new insights into the pathogenesis of SARS, demonstrating the important role of CD4(+) but not CD8(+) T cells in primary SARS-CoV infection in this model.