Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Emory Children's Center for Transplantation and Immuno-mediated Disorders, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
FEBS Lett. 2019 Dec;593(24):3461-3483. doi: 10.1002/1873-3468.13696. Epub 2019 Dec 8.
Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.
腺病毒是一种高度进化成功的病原体，广泛存在于动物界，感染的宿主范围从蜥蜴和青蛙到海豚、鸟类和人类。尽管人类自然感染腺病毒很少引起严重的病理变化，但静脉内注射高剂量的腺病毒载体会迅速激活先天免疫系统，导致细胞因子风暴综合征、弥散性血管内凝血、血小板减少和肝毒性，这些因素单独或联合作用可能导致发病率和死亡率。关于腺病毒如何激活先天免疫系统的确切信息主要来自于小鼠实验系统。将腺病毒静脉内给药于小鼠，揭示了先天免疫的细胞和分子成分如何识别腺病毒颗粒，激活促炎信号通路和细胞因子产生，将腺病毒颗粒从血液中隔离，并清除感染腺病毒的细胞。总的来说，这些信息极大地提高了我们对先天免疫激活机制的认识，也为设计更安全的腺病毒载体用于治疗遗传和获得性人类疾病铺平了道路。
