Respiratory syncytial virus fusion protein promotes TLR-4-dependent neutrophil extracellular trap formation by human neutrophils.
Respiratory syncytial virus fusion protein promotes TLR-4-dependent neutrophil extracellular trap formation by human neutrophils.
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DOI：
10.1371/journal.pone.0124082
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Porto BN
中科院分区：
文献类型：
--
作者：
Funchal GA;Jaeger N;Czepielewski RS;Machado MS;Muraro SP;Stein RT;Bonorino CB;Porto BN
呼吸道合胞病毒(RSV)引起的急性病毒性毛细支气管炎是出生一岁儿童最常见的呼吸道疾病。呼吸道合胞病毒毛细支气管炎造成大量住院治疗，并对卫生系统造成重要负担。中性粒细胞及其产物存在于呼吸道合胞病毒感染患者的呼吸道中，这些患者发展为肺部疾病加重。中性粒细胞胞外陷阱(NETs)是中性粒细胞在不同刺激下在胞外释放的颗粒和核内容物，最近的研究提出了Net在病毒感染中的作用。在这项研究中，我们证明了RSV颗粒和RSV融合蛋白都能够诱导人中性粒细胞形成网络。此外，我们还分析了RSV融合蛋白诱导网络形成的机制。RSV F蛋白能以浓度依赖的方式诱导净释放，中性粒细胞弹性蛋白酶和髓过氧化物酶在DNA纤维上均有表达，DNA酶可将F蛋白诱导的Net分解，证实其骨架为染色质。这种病毒蛋白依赖于TLR-4的激活、NADPH氧化酶衍生的ROS的产生以及ERK和p38MAPK的磷酸化而导致细胞外DNA的释放。综上所述，这些结果表明F蛋白激活了一条协调的信号通路，导致了净生产。呼吸道合胞病毒感染中大量产生的Net可能会加重幼儿和婴儿感染的炎症症状。我们认为，以F蛋白结合TLR-4为靶点可能会导致新的治疗方法，以帮助控制RSV诱导的炎症后果和病毒性毛细支气管炎的病理。
Acute viral bronchiolitis by Respiratory Syncytial Virus (RSV) is the most common respiratory illness in children in the first year of life. RSV bronchiolitis generates large numbers of hospitalizations and an important burden to health systems. Neutrophils and their products are present in the airways of RSV-infected patients who developed increased lung disease. Neutrophil Extracellular Traps (NETs) are formed by the release of granular and nuclear contents of neutrophils in the extracellular space in response to different stimuli and recent studies have proposed a role for NETs in viral infections. In this study, we show that RSV particles and RSV Fusion protein were both capable of inducing NET formation by human neutrophils. Moreover, we analyzed the mechanisms involved in RSV Fusion protein-induced NET formation. RSV F protein was able to induce NET release in a concentration-dependent fashion with both neutrophil elastase and myeloperoxidase expressed on DNA fibers and F protein-induced NETs was dismantled by DNase treatment, confirming that their backbone is chromatin. This viral protein caused the release of extracellular DNA dependent on TLR-4 activation, NADPH Oxidase-derived ROS production and ERK and p38 MAPK phosphorylation. Together, these results demonstrate a coordinated signaling pathway activated by F protein that led to NET production. The massive production of NETs in RSV infection could aggravate the inflammatory symptoms of the infection in young children and babies. We propose that targeting the binding of TLR-4 by F protein could potentially lead to novel therapeutic approaches to help control RSV-induced inflammatory consequences and pathology of viral bronchiolitis.
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DOI：
10.1073/pnas.0900226106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Guimaraes-Costa, Anderson B.;Nascimento, Michelle T. C.;Saraiva, Elvira M.
通讯作者：
Saraiva, Elvira M.
影响因子：
5.8
作者：
McCormick, Allison;Heesemann, Leonie;Ebel, Frank
通讯作者：
Ebel, Frank
DOI：
10.4049/jimmunol.1201719
发表时间：
2012-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kaplan MJ;Radic M
通讯作者：
Radic M
影响因子：
5
作者：
Fujie, K;Shinguh, Y;Okuhara, M
通讯作者：
Okuhara, M
影响因子：
3.7
作者：
Kahn, JS;Schnell, MJ;Rose, JK
通讯作者：
Rose, JK