Hendra virus is an emerging virus with a geographically broad host reservoir. In humans, Hendra virus causes excessive inflammatory disease of the lung and nervous system. Our current understanding as to how Hendra virus or what factors induce inflammation is limited and as such, there are currently no therapeutic options available for patients who contract Hendra virus. Recent studies have identified viral aggregating proteins as drivers of inflammation in influenza A virus and SARS-CoV-2 virus. In this study, we sought to identify potential aggregating Hendra virus proteins as proof-of-concept that inflammasome activation may induce inflammation and contribute to disease pathology. Here, we have identified that a peptide analogue of Hendra virus C protein (termed HeVc) forms aggregates and activates the NLRP3 inflammasome through phagocytic uptake into cells in vitro. Treatment of cells with the specific NLRP3 inhibitor MCC950 ameliorated IL-1β secretion responses in vitro. Critically, in vivo intranasal inoculation of mice with aggregated HeVc peptide induced pulmonary inflammation, suggesting HeVc may drive immunopathology during infection. Importantly, mice treated with MCC950 demonstrated reduced IL-1β secretion into the bronchoalveolar space, highlighting the role of NLRP3 in host HeV infections and a potential therapeutic strategy to reduce disease pathology. Taken together, these results identify Hendra virus C protein as a possible contributor to immunopathology during Hendra virus infections. Importantly, these studies highlight a potential role for NLRP3 in driving disease-associated inflammation, critically identifying a possible therapeutic strategy to alleviate disease-associated inflammation of infected patients through targeting of the NLRP3 inflammasome.

中文翻译：

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聚集的亨德拉病毒 C 蛋白激活 NLRP3 炎症小体诱导炎症

亨德拉病毒是一种新兴病毒，具有广泛的宿主地理储库。在人类中，亨德拉病毒会导致肺部和神经系统过度炎症性疾病。我们目前对亨德拉病毒如何或哪些因素诱发炎症的了解有限，因此，目前没有针对感染亨德拉病毒的患者的治疗选择。最近的研究发现病毒聚集蛋白是甲型流感病毒和 SARS-CoV-2 病毒炎症的驱动因素。在这项研究中，我们试图鉴定潜在的聚集亨德拉病毒蛋白，作为炎性体激活可能诱发炎症并促进疾病病理学的概念证明。在这里，我们发现亨德拉病毒 C 蛋白的肽类似物（称为 HeVc）在体外形成聚集体并通过细胞吞噬吞噬激活 NLRP3 炎症小体。用特异性 NLRP3 抑制剂 MCC950 处理细胞可改善体外 IL-1β 分泌反应。重要的是，用聚集的HeVc肽对小鼠进行体内鼻内接种诱导了肺部炎症，这表明HeVc可能在感染期间驱动免疫病理学。重要的是，用 MCC950 治疗的小鼠表现出向支气管肺泡腔的 IL-1β 分泌减少，突出了 NLRP3 在宿主 HeV 感染中的作用以及减少疾病病理的潜在治疗策略。综上所述，这些结果表明亨德拉病毒 C 蛋白可能是亨德拉病毒感染期间免疫病理学的一个贡献者。重要的是，这些研究强调了 NLRP3 在驱动疾病相关炎症中的潜在作用，批判性地确定了一种可能的治疗策略，通过靶向 NLRP3 炎性体来减轻感染患者的疾病相关炎症。