Liu Jun, Trefry John C, Babka April M, Schellhase Christopher W, Coffin Kayla M, Williams Janice A, Raymond Jo Lynne W, Facemire Paul R, Chance Taylor B, Davis Neil M, Scruggs Jennifer L, Rossi Franco D, Haddow Andrew D, Zelko Justine M, Bixler Sandra L, Crozier Ian, Iversen Patrick L, Pitt Margaret L, Kuhn Jens H, Palacios Gustavo, Zeng Xiankun
United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, MD 21702, USA.
Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Sci Transl Med. 2022 Feb 9;14(631):eabi5229. doi: 10.1126/scitranslmed.abi5229.
Effective therapeutics have been developed against acute Ebola virus disease (EVD) in both humans and experimentally infected nonhuman primates. However, the risk of viral persistence and associated disease recrudescence in survivors receiving these therapeutics remains unclear. In contrast to rhesus macaques that survived Ebola virus (EBOV) exposure in the absence of treatment, we discovered that EBOV, despite being cleared from all other organs, persisted in the brain ventricular system of rhesus macaque survivors that had received monoclonal antibody (mAb) treatment. In mAb-treated macaque survivors, EBOV persisted in macrophages infiltrating the brain ventricular system, including the choroid plexuses. This macrophage infiltration was accompanied by severe tissue damage, including ventriculitis, choroid plexitis, and meningoencephalitis. Specifically, choroid plexus endothelium-derived EBOV infection led to viral persistence in the macaque brain ventricular system. This resulted in apoptosis of ependymal cells, which constitute the blood-cerebrospinal fluid barrier of the choroid plexuses. Fatal brain-confined recrudescence of EBOV infection manifested as severe inflammation, local pathology, and widespread infection of the ventricular system and adjacent neuropil in some of the mAb-treated macaque survivors. This study highlights organ-specific EBOV persistence and fatal recrudescent disease in rhesus macaque survivors after therapeutic treatment and has implications for the long-term follow-up of human survivors of EVD.
针对人类急性埃博拉病毒病（EVD）以及实验感染的非人类灵长类动物，已研发出有效的治疗方法。然而，接受这些治疗的幸存者中病毒持续存在及相关疾病复发的风险仍不明确。与未经治疗而在接触埃博拉病毒（EBOV）后存活下来的恒河猴不同，我们发现，尽管EBOV已从所有其他器官清除，但在接受单克隆抗体（mAb）治疗的恒河猴幸存者的脑室系统中仍持续存在。在接受mAb治疗的猕猴幸存者中，EBOV在浸润脑室系统（包括脉络丛）的巨噬细胞中持续存在。这种巨噬细胞浸润伴随着严重的组织损伤，包括脑室炎、脉络丛炎和脑膜脑炎。具体而言，脉络丛内皮细胞衍生的EBOV感染导致EBOV在猕猴脑室系统中持续存在。这导致室管膜细胞凋亡，室管膜细胞构成脉络丛的血脑脊髓液屏障。在一些接受mAb治疗的猕猴幸存者中，EBOV感染的致命性脑部复发表现为严重炎症、局部病理变化以及脑室系统和邻近神经纤维网的广泛感染。这项研究突出了治疗后恒河猴幸存者中EBOV在器官特异性的持续存在和致命的复发疾病，对EVD人类幸存者的长期随访具有启示意义。
