Dynamics of Sendai Virus Spread, Clearance, and Immunotherapeutic Efficacy after Hematopoietic Cell Transplant Imaged Noninvasively in Mice.
Dynamics of Sendai Virus Spread, Clearance, and Immunotherapeutic Efficacy after Hematopoietic Cell Transplant Imaged Noninvasively in Mice.
复制标题
小鼠造血细胞移植后仙台病毒传播、清除和免疫治疗效果的动态变化。
DOI：
10.1128/jvi.01705-17
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发表时间：
2018
影响因子：
5.4
通讯作者：
Russell,CharlesJ
中科院分区：
文献类型：
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作者：
Mostafa,HebaH;Vogel,Peter;Srinivasan,Ashok;Russell,CharlesJ
目前还没有针对人副流感病毒（HPIV）的获批疫苗或病毒特异性治疗方法，这些病毒最近被重新分类为人呼吸道病毒1型、人呼吸道病毒3型、人风疹病毒2型和人风疹病毒4型。这些病毒导致免疫功能低下患者的发病率和死亡率，包括那些接受造血细胞移植（HCT）。没有小动物模型的非侵入性成像的呼吸道病毒感染的HCT主机存在，尽管效用，这样的系统将提供监测长期感染，其清除，和治疗方案。我们使用了一种表达端粒酶的报告病毒，在小鼠中对鼠呼吸道病毒（仙台病毒株[SeV]）（HPIV 1的鼠对应物）的感染进行非侵入性成像。与疾病严重程度无关，感染的清除在HCT后约21天开始，主要是由于CD 8 +T细胞的恢复。粒细胞集落刺激因子（G-CSF）和自然杀伤（NK）细胞过继转移的免疫治疗提供了有限的治疗获益。用融合蛋白（F）特异性单克隆抗体治疗可阻止肺部感染的传播，即使治疗延迟至感染后10天也可降低疾病的严重程度，但对上呼吸道感染几乎没有明显影响。病毒特异性T细胞在感染后10天的连续转移加速了5天的清除，降低了整个呼吸道的感染程度，并降低了疾病的严重程度。总体而言，结果支持使用单克隆抗体和过继性T细胞转移临床治疗HCT宿主中呼吸道病毒感染的研究;该成像系统应该可扩展到其它呼吸道病毒，例如呼吸道合胞病毒和流感病毒。重要的是副流感病毒是免疫功能低下的宿主中由于呼吸道病毒感染而引起的疾病和死亡的主要原因，包括接受骨髓移植的患者。目前尚无有效的治疗措施。我们对正在接受骨髓移植并感染仙台病毒（一种鼠副流感病毒（呼吸道病毒））的小鼠进行了非侵入性成像。我们首次展示了过继性T细胞治疗和融合（F）蛋白单克隆抗体治疗在清除呼吸道仙台病毒和降低疾病严重程度方面的治疗窗口。小鼠耐受这些治疗，没有任何可检测的毒性。这些发现为评估T细胞疗法对抗人类副流感病毒的安全性的研究铺平了道路。针对人类其他血液传播病毒的免疫性T细胞疗法已被证明是安全有效的。我们在接受骨髓移植的小鼠中的非侵入性成像模型可能非常适合于跟踪其他呼吸道病毒感染并开发新的预防和治疗策略。
There are no approved vaccines or virus-specific treatments for human parainfluenza viruses (HPIVs), which have recently been reclassified into the species Human respirovirus 1, Human respirovirus 3, Human rubulavirus 2, and Human rubulavirus 4. These viruses cause morbidity and mortality in immunocompromised patients, including those undergoing hematopoietic cell transplant (HCT). No small-animal models for noninvasive imaging of respiratory virus infection in the HCT host exist, despite the utility that such a system would offer to monitor prolonged infection, its clearance, and treatment options. We used a luciferase-expressing reporter virus to noninvasively image in mice the infection of murine respirovirus (strain Sendai virus [SeV]), the murine counterpart of HPIV1. Independent of disease severity, the clearance of infection began approximately 21 days after HCT, largely due to the recovery of CD8+T cells. Immunotherapy with granulocyte colony-stimulating factor (G-CSF) and adoptive transfer of natural killer (NK) cells provided a limited therapeutic benefit. Treatment with a fusion (F) protein-specific monoclonal antibody arrested the spread of lung infection and reduced the disease severity even when treatment was delayed to up to 10 days postinfection but had little observable effect on upper respiratory tract infection. Adoptive transfer of virus-specific T cells at 10 days postinfection accelerated the clearance by 5 days, reduced the extent of infection throughout the respiratory tract, and reduced the disease severity. Overall, the results support investigation of the clinical treatment of respiratory virus infection in the HCT host with monoclonal antibodies and adoptive T-cell transfer; the imaging system should be extendable to other respiratory viruses, such as respiratory syncytial virus and influenza virus.IMPORTANCEParainfluenza viruses are a major cause of disease and death due to respiratory virus infection in the immunocompromised host, including those undergoing bone marrow transplantation. There are currently no effective treatment measures. We noninvasively imaged mice that were undergoing a bone marrow transplant and infected with Sendai virus, a murine parainfluenza virus (respirovirus). For the first time, we show the therapeutic windows of adoptive T-cell therapy and treatment with a monoclonal antibody to the fusion (F) protein in clearing Sendai virus from the respiratory tract and reducing disease severity. Mice tolerated these treatments without any detectable toxicity. These findings pave the way for studies assessing the safety of T-cell therapy against parainfluenza virus in humans. Adoptive T-cell therapy against other blood-borne viruses in humans has been shown to be safe and effective. Our model of noninvasive imaging in mice that had undergone a bone marrow transplant may be well suited to track other respiratory virus infections and develop novel preventive and therapeutic strategies.