Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily
Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily
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DOI：
10.1016/s0165-2478(01)00327-3
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发表时间：
2002-03-01
影响因子：
4.4
通讯作者：
Geisbert, TW
中科院分区：
文献类型：
--
作者：
Hensley, LE;Young, HA;Geisbert, TW
埃博拉病毒（EBOV）感染的特征在于正常宿主免疫应答的失调。对该机制的了解来自最近在非人灵长类动物中的研究，该研究表明EBOV感染单核吞噬细胞系统（MPS）的细胞，导致旁观者淋巴细胞凋亡。在这项研究中，我们评估了EBOV感染的非人灵长类动物的细胞因子/趋化因子的血清水平，作为这种旁观者凋亡的可能相关因素。在所有感染EBOV的猴中观察到干扰素（IFN）-α、IFN-β、白细胞介素（IL）-6、IL-18、MIP-1 α和MIP-1 β水平升高，表明发生了强烈的促炎反应。为了探讨淋巴细胞凋亡的机制，测定了可溶性Fas（sFas）和硝酸盐积累。在4/9只动物中检测到sFas，而在3/3只动物中发生硝酸盐积累升高。为了进一步评价这些因子在观察到的旁观者细胞凋亡和完整动物中的潜在作用，制备粘附的人单核细胞/巨噬细胞（PHM）和单核细胞的体外培养物。分化为未成熟的树突状细胞（DC）。用EBOV感染这些培养物，并分析细胞因子/趋化因子诱导和凋亡相关基因的表达。此外，EBOV体外感染外周血单核细胞（PBMC）导致细胞因子/趋化因子诱导强烈，乳酸脱氢酶（LDH）活性显着增加，电子显微镜检查的凋亡淋巴细胞数量增加。在PHM培养物中检测到sFAS水平升高，尽管通过免疫组织化学、RNA分析和流式细胞术检测到90%的EBOV感染的PHM对肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）呈阳性。灭活的EBOV也影响PHM中TRAIL表达的增加，表明TNF受体超家族可能参与宿主淋巴细胞的凋亡，并且诱导可能独立于病毒复制而发生。在进一步的研究与感染PHM，MHC II的表达显着抑制后6天，免疫失调的另一个相关。总之，我们的研究结果表明，单核吞噬细胞的感染是至关重要的，触发级联事件涉及细胞因子/趋化因子和氧自由基。这是这些事件的结果，而不是直接的病毒感染，导致许多观察到的病理学。鉴定细胞因子/趋化因子、一氧化氮和活性氧参与所观察到的丝状病毒发病机制可能有助于深入了解丝状病毒发病机制的治疗对策的合理设计。(C)2002 Elsevier Science B. V.保留所有权利。
Ebola virus (EBOV) infections are characterized by dysregulation of normal host immune responses. Insight into the mechanism came from recent studies in nonhuman primates, which showed that EBOV infects cells of the mononuclear phagocyte system (MPS), resulting in apoptosis of bystander lymphocytes. In this study, we evaluated serum levels of cytokines/chemokines in EBOV-infected nonhuman primates, as possible correlates of this bystander apoptosis. Increased levels of interferon (IFN)-alpha, IFN-beta, interleukin (IL)-6, IL-18, MIP-1alpha, and MIP-1beta were observed in all EBOV-infected monkeys, indicating the occurrence of a strong proinflammatory response. To investigate the mechanism(s) involved in lymphoid apoptosis, soluble Fas (sFas) and nitrate accumulation were measured. sFas was detected in 4/9 animals, while, elevations of nitrate accumulation occurred in 3/3 animals. To further evaluate the potential role of these factors in the observed bystander apoptosis and intact animals, in vitro cultures were prepared of adherent human monocytes/macrophages (PHM), and monocytes. differentiated into immature dendritic cells (DC). These cultures were infected with EBOV and analyzed for cytokine/chemokine induction and expression of apoptosis-related genes. In addition, the in vitro EBOV infection of peripheral blood mononuclear cells (PBMC) resulted in strong cytokine/chemokine induction, a marked increase in lactate dehydrogenase (LDH) activity, and an increase in the number of apoptotic lymphocytes examined by electron microscopy. Increased levels of sFAS were detected in PHM cultures, although, 90% of EBOV-infected PHM were positive for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by immunohistochemistry, RNA analysis, and flow cytometry. Inactivated EBOV also effected increased TRAIL expression in PHM, suggesting that the TNF receptor superfamily may be involved in apoptosis of the host lymphoid cells, and that induction may occur independent of viral replication. In further studies with infected PHM, expression of MHC II was remarkably suppressed after 6 days, an additional correlate of immunological dysregulation. In conclusion, our findings suggest that infection of mononuclear phagocytes is critical, triggering a cascade of events involving cytokines/chemokines and oxygen free radicals. It is the consequence of these events rather than direct viral infection that results in much of the observed pathology. Identification of cytokine/chemokine, nitric oxide, and reactive oxygen species involvement in the observed filoviral pathogenesis may lend insight into the rational design of therapeutic countermeasures of filoviral pathogenesis. (C) 2002 Elsevier Science B.V. All rights reserved.