Virus-Specific Memory CD8 T Cells Provide Substantial Protection from Lethal Severe Acute Respiratory Syndrome Coronavirus Infection
Virus-Specific Memory CD8 T Cells Provide Substantial Protection from Lethal Severe Acute Respiratory Syndrome Coronavirus Infection
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DOI：
10.1128/jvi.01505-14
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Perlman, Stanley
中科院分区：
文献类型：
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作者：
Channappanavar, Rudragouda;Fett, Craig;Perlman, Stanley
严重急性呼吸综合征冠状病毒（SARS-CoV）在 2002 年至 2003 年期间引起了一种发病率和死亡率很高的急性人类呼吸道疾病。几项研究已经证明了刺突 (S) 糖蛋白诱导的中和抗体在保护易感宿主免受致命感染方面的作用。然而，在从 SARS 中恢复的患者中，抗 SARS-CoV 抗体反应的持续时间很短，因此开发额外的疫苗策略至关重要。 SARS-CoV 特异性记忆 CD8 T 细胞在 SARS-CoV 感染后持续存在长达 6 年，在此期间，从 SARS 中恢复的个体中检测不到记忆 B 细胞和抗病毒抗体。在这项研究中，我们评估了在缺乏 SARS-CoV 特异性记忆 CD4 T 细胞或 B 细胞的情况下，病毒特异性记忆 CD8 T 细胞介导预防感染的能力。我们证明，对单一免疫显性表位（S436 或 S525）具有特异性的记忆 CD8 T 细胞可显着保护 8 至 10 个月大的小鼠免受致命的 SARS-CoV 感染。使用负载肽的树突状细胞 (DC) 进行静脉内免疫，然后使用编码 S436 或 S525 的重组痘苗病毒 (rVV) 鼻内加强免疫，导致支气管肺泡灌洗液 (BAL)、肺和脾中病毒特异性记忆 CD8 T 细胞的积累。在受到致死剂量的 SARS-CoV 攻击后，病毒特异性记忆 CD8 T 细胞有效产生多种效应细胞因子（γ 干扰素 [IFN-γ]、肿瘤坏死因子 α [TNF-α] 和白细胞介素 2 [IL-2]）和溶细胞分子（颗粒酶 B）并减少肺部病毒载量。总体而言，我们的结果表明，SARS-CoV 特异性记忆 CD8 T 细胞可以保护易感宿主免受致命的 SARS-CoV 感染，但它们也表明 SARS-CoV 特异性 CD4 T 细胞和抗体反应对于完全保护是必要的。然而，之前尚未研究过 SARS-CoV 特异性记忆 CD8 T 细胞在 SARS-CoV 攻击后介导保护中的作用。在这项研究中，我们采用初免-加强免疫方法，证明病毒特异性 CD8 T 细胞可以保护易感的 8 至 10 个月大的小鼠免受致命的 SARS-CoV 攻击。因此，未来针对新出现的冠状病毒的疫苗应强调记忆 CD8 T 细胞反应的产生，以实现最佳保护。
Severe acute respiratory syndrome coronavirus (SARS-CoV) caused an acute human respiratory illness with high morbidity and mortality in 2002-2003. Several studies have demonstrated the role of neutralizing antibodies induced by the spike (S) glycoprotein in protecting susceptible hosts from lethal infection. However, the anti-SARS-CoV antibody response is short-lived in patients who have recovered from SARS, making it critical to develop additional vaccine strategies. SARS-CoV-specific memory CD8 T cells persisted for up to 6 years after SARS-CoV infection, a time at which memory B cells and antivirus antibodies were undetectable in individuals who had recovered from SARS. In this study, we assessed the ability of virus-specific memory CD8 T cells to mediate protection against infection in the absence of SARS-CoV-specific memory CD4 T or B cells. We demonstrate that memory CD8 T cells specific for a single immunodominant epitope (S436 or S525) substantially protected 8- to 10-month-old mice from lethal SARS-CoV infection. Intravenous immunization with peptide-loaded dendritic cells (DCs) followed by intranasal boosting with recombinant vaccinia virus (rVV) encoding S436 or S525 resulted in accumulation of virus-specific memory CD8 T cells in bronchoalveolar lavage fluid (BAL), lungs, and spleen. Upon challenge with a lethal dose of SARS-CoV, virus-specific memory CD8 T cells efficiently produced multiple effector cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha],and interleukin 2 [IL-2]) and cytolytic molecules (granzyme B) and reduced lung viral loads. Overall, our results show that SARS-CoV-specific memory CD8 T cells protect susceptible hosts from lethal SARS-CoV infection, but they also suggest that SARS-CoV-specific CD4 T cell and antibody responses are necessary for complete protection.IMPORTANCEVirus-specific CD8 T cells are required for pathogen clearance following primary SARS-CoV infection. However, the role of SARS-CoV-specific memory CD8 T cells in mediating protection after SARS-CoV challenge has not been previously investigated. In this study, using a prime-boost immunization approach, we showed that virus-specific CD8 T cells protect susceptible 8- to 10-month-old mice from lethal SARS-CoV challenge. Thus, future vaccines against emerging coronaviruses should emphasize the generation of a memory CD8 T cell response for optimal protection.