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埃博拉病毒蛋白 VP40 刺激人自然杀伤细胞依赖 IL-12 和 IL-18 的激活。

Ebola virus protein VP40 stimulates IL-12- and IL-18-dependent activation of human natural killer cells.

机构信息

Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

出版信息

JCI Insight. 2022 Aug 22;7(16):e158902. doi: 10.1172/jci.insight.158902.

DOI:10.1172/jci.insight.158902
PMID:35862204
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9462474/
Abstract

Accumulation of activated natural killer (NK) cells in tissues during Ebola virus infection contributes to Ebola virus disease (EVD) pathogenesis. Yet, immunization with Ebola virus-like particles (VLPs) comprising glycoprotein and matrix protein VP40 provides rapid, NK cell-mediated protection against Ebola challenge. We used Ebola VLPs as the viral surrogates to elucidate the molecular mechanism by which Ebola virus triggers heightened NK cell activity. Incubation of human peripheral blood mononuclear cells with Ebola VLPs or VP40 protein led to increased expression of IFN-γ, TNF-α, granzyme B, and perforin by CD3-CD56+ NK cells, along with increases in degranulation and cytotoxic activity of these cells. Optimal activation required accessory cells like CD14+ myeloid and CD14- cells and triggered increased secretion of numerous inflammatory cytokines. VP40-induced IFN-γ and TNF-α secretion by NK cells was dependent on IL-12 and IL-18 and suppressed by IL-10. In contrast, their increased degranulation was dependent on IL-12 with little influence of IL-18 or IL-10. These results demonstrate that Ebola VP40 stimulates NK cell functions in an IL-12- and IL-18-dependent manner that involves CD14+ and CD14- accessory cells. These potentially novel findings may help in designing improved intervention strategies required to control viral transmission during Ebola outbreaks.

摘要

在埃博拉病毒感染期间，激活的自然杀伤 (NK) 细胞在组织中的积累导致埃博拉病毒病 (EVD) 的发病机制。然而，用包含糖蛋白和基质蛋白 VP40 的埃博拉病毒样颗粒 (VLPs) 进行免疫接种可迅速提供针对埃博拉病毒挑战的 NK 细胞介导的保护。我们使用埃博拉 VLPs 作为病毒替代物，阐明埃博拉病毒引发 NK 细胞活性增强的分子机制。用埃博拉 VLPs 或 VP40 蛋白孵育人外周血单核细胞会导致 CD3-CD56+ NK 细胞表达 IFN-γ、TNF-α、颗粒酶 B 和穿孔素增加，同时这些细胞的脱颗粒和细胞毒性活性增加。最佳激活需要辅助细胞，如 CD14+ 髓样细胞和 CD14-细胞，并触发许多炎症细胞因子的分泌增加。VP40 诱导的 NK 细胞 IFN-γ 和 TNF-α 分泌依赖于 IL-12 和 IL-18，并受 IL-10 抑制。相比之下，它们增加的脱颗粒依赖于 IL-12，IL-18 或 IL-10 的影响很小。这些结果表明，埃博拉病毒 VP40 以依赖于 IL-12 和 IL-18 的方式刺激 NK 细胞功能，涉及 CD14+ 和 CD14-辅助细胞。这些潜在的新发现可能有助于设计改进的干预策略，以控制埃博拉疫情期间的病毒传播。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/29642cbaf57b/jciinsight-7-158902-g213.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/e3c6f9e982fa/jciinsight-7-158902-g205.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/42a1ce987453/jciinsight-7-158902-g206.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/75c0f051d093/jciinsight-7-158902-g207.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/686281cd36a4/jciinsight-7-158902-g208.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/4389080dbec2/jciinsight-7-158902-g209.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/703d608d31bb/jciinsight-7-158902-g210.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/12906b547614/jciinsight-7-158902-g211.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/56e72878734e/jciinsight-7-158902-g212.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/29642cbaf57b/jciinsight-7-158902-g213.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/e3c6f9e982fa/jciinsight-7-158902-g205.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/42a1ce987453/jciinsight-7-158902-g206.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/75c0f051d093/jciinsight-7-158902-g207.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/686281cd36a4/jciinsight-7-158902-g208.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/4389080dbec2/jciinsight-7-158902-g209.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/703d608d31bb/jciinsight-7-158902-g210.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/12906b547614/jciinsight-7-158902-g211.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/56e72878734e/jciinsight-7-158902-g212.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e73/9462474/29642cbaf57b/jciinsight-7-158902-g213.jpg

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