PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology.
PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology.
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DOI：
10.1371/journal.ppat.1001014
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发表时间：
2010-07-22
期刊：
影响因子：
6.7
通讯作者：
McCullers JA
中科院分区：
文献类型：
--
作者：
McAuley JL;Chipuk JE;Boyd KL;Van De Velde N;Green DR;McCullers JA
随着最近出现一种新型大流行毒株，目前人们对了解流感病毒毒力的分子特征产生了浓厚的兴趣。研究了流行病学上重要的甲型流感病毒株的 PB1-F2 蛋白，以确定它们的功能和对毒力的贡献。使用源自 PB1-F2 C 端序列的 27 聚体肽和在共同背景下设计的嵌合病毒，我们证明通过 PB1-F2 诱导细胞死亡依赖于 BAK/BAX 介导的线粒体细胞色素 c 释放。该功能是 A/Puerto Rico/8/34 的 PB1-F2 蛋白特有的，使用源自过去大流行病毒株的 PB1-F2 肽时未发现该功能。然而，来自 20 世纪三种大流行毒株和 H5N1 亚型高致病性毒株的 PB1-F2 蛋白被证明可以增强肺部炎症反应，导致病理加重。最近流行的季节性甲型流感毒株不具有这种促炎功能，因为在人类适应过程中通过截短或突变而失去了PB1-F2蛋白的免疫刺激活性。这些数据表明，当 PB1 基因片段最近来自禽类宿主时，PB1-F2 蛋白有助于大流行毒株的毒力。目前人们对了解流感病毒如何引起疾病非常感兴趣。在本文中，我们探讨了流感病毒 PB1-F2 蛋白在疾病中的作用。我们表明，该蛋白质导致细胞死亡的能力是通过由 BAX 或 BAK 蛋白质控制的线粒体死亡途径介导的。然而，该蛋白质的这种功能似乎只与一组有限的病毒有关，与过去的大流行病毒株无关。相反，事实证明，在肺部产生炎症的能力是所有过去大流行毒株以及 H5N1 高致病性禽流感毒株的共同特征，而 H5N1 高致病性禽流感毒株仍然是重大大流行威胁。这种促炎表型似乎是从禽类宿主中出现的病毒的一个特征，因此对于跨越物种屏障并在人类中扎根的新病毒株非常重要。在哺乳动物肺部的循环和适应过程中，这种功能通常会丧失。值得注意的是，2009 年 H1N1 大流行病毒株不表达全长 PB1-F2。如果通过重配获得功能齐全的炎症性 PB1-F2，这可能预示着疾病潜力的大大增强。
With the recent emergence of a novel pandemic strain, there is presently intense interest in understanding the molecular signatures of virulence of influenza viruses. PB1-F2 proteins from epidemiologically important influenza A virus strains were studied to determine their function and contribution to virulence. Using 27-mer peptides derived from the C-terminal sequence of PB1-F2 and chimeric viruses engineered on a common background, we demonstrated that induction of cell death through PB1-F2 is dependent upon BAK/BAX mediated cytochrome c release from mitochondria. This function was specific for the PB1-F2 protein of A/Puerto Rico/8/34 and was not seen using PB1-F2 peptides derived from past pandemic strains. However, PB1-F2 proteins from the three pandemic strains of the 20th century and a highly pathogenic strain of the H5N1 subtype were shown to enhance the lung inflammatory response resulting in increased pathology. Recently circulating seasonal influenza A strains were not capable of this pro-inflammatory function, having lost the PB1-F2 protein's immunostimulatory activity through truncation or mutation during adaptation in humans. These data suggest that the PB1-F2 protein contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from the avian reservoir. There is presently great interest in understanding how influenza viruses cause disease. In this paper, we explore the role of the influenza virus PB1-F2 protein in disease. We show that the ability of the protein to cause cell death is mediated through a mitochondrial death pathway controlled by proteins called BAX or BAK. However, this function of the protein only seems to be relevant to a restricted set of viruses and not past pandemic strains. Instead, the ability to generate inflammation in the lung proves to be a common trait of all past pandemic strains as well as the H5N1 highly pathogenic avian influenza strains which remain a significant pandemic threat. It appears likely that this pro-inflammatory phenotype is a characteristic of viruses emerging from the avian reservoir and is therefore important for new strains that cross the species barrier and establish themselves in humans. During circulation and adaptation in the mammalian lung, this function is typically lost. Of note, the novel 2009 H1N1 pandemic strain does not express a full-length PB1-F2. Were it to acquire a fully functional, inflammatory PB1-F2 through reassortment, this could herald greatly enhanced disease potential.
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DOI：
10.1086/591708
发表时间：
2008-10-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Morens DM;Taubenberger JK;Fauci AS
通讯作者：
Fauci AS
DOI：
10.1016/j.jcv.2009.06.006
发表时间：
2009-07
期刊：
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
影响因子：
--
作者：
Peiris JS;Poon LL;Guan Y
通讯作者：
Guan Y
DOI：
10.1097/inf.0b013e3181684d41
发表时间：
2008-10
期刊：
The Pediatric infectious disease journal
影响因子：
--
作者：
McCullers JA
通讯作者：
McCullers JA
DOI：
10.1073/pnas.0711682102
发表时间：
2008-02-12
影响因子：
11.1
作者：
La Gruta, Nicole L.;Thomas, Paul G.;Turner, Stephen J.
通讯作者：
Turner, Stephen J.
影响因子：
2.1
作者：
Roeder, Rene;Bruns, Karsten;Schubert, Ulrich
通讯作者：
Schubert, Ulrich