Mostafa Heba H, Vogel Peter, Srinivasan Ashok, Russell Charles J
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
J Virol. 2018 Jan 2;92(2). doi: 10.1128/JVI.01705-17. Print 2018 Jan 15.
There are no approved vaccines or virus-specific treatments for human parainfluenza viruses (HPIVs), which have recently been reclassified into the species , , , and 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. Parainfluenza 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.
目前尚无获批用于人类副流感病毒（HPIV）的疫苗或针对病毒的特异性治疗方法，这些病毒最近已被重新分类为、、和物种。这些病毒会导致免疫功能低下的患者发病和死亡，包括接受造血细胞移植（HCT）的患者。尽管这样的系统对于监测长期感染、其清除情况以及治疗方案具有重要作用，但目前尚无用于HCT宿主呼吸道病毒感染无创成像的小动物模型。我们使用表达荧光素酶的报告病毒对小鼠体内的鼠肺病毒（仙台病毒[SeV]株）感染进行无创成像，鼠肺病毒是HPIV1的鼠类对应物。与疾病严重程度无关，感染清除在HCT后约21天开始，这主要归因于CD8 T细胞的恢复。用粒细胞集落刺激因子（G-CSF）进行免疫治疗和自然杀伤（NK）细胞的过继转移提供了有限的治疗益处。用融合（F）蛋白特异性单克隆抗体治疗可阻止肺部感染的扩散并降低疾病严重程度，即使治疗延迟至感染后长达10天，但对上呼吸道感染几乎没有明显影响。在感染后10天过继转移病毒特异性T细胞可使清除加快5天，减少整个呼吸道的感染程度，并降低疾病严重程度。总体而言，这些结果支持对用单克隆抗体和过继性T细胞转移治疗HCT宿主呼吸道病毒感染进行临床研究；该成像系统应可扩展到其他呼吸道病毒，如呼吸道合胞病毒和流感病毒。副流感病毒是免疫功能低下宿主（包括接受骨髓移植的宿主）因呼吸道病毒感染导致疾病和死亡的主要原因。目前尚无有效的治疗措施。我们对接受骨髓移植并感染鼠副流感病毒（肺病毒）仙台病毒的小鼠进行了无创成像。我们首次展示了过继性T细胞疗法和用融合（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。小鼠耐受这些治疗且未检测到任何毒性。这些发现为评估针对人类副流感病毒的T细胞疗法安全性的研究铺平了道路。已证明针对人类其他血源病毒的过继性T细胞疗法是安全有效的。我们对接受骨髓移植的小鼠进行无创成像的模型可能非常适合追踪其他呼吸道病毒感染并制定新的预防和治疗策略。
