Transcriptomic analysis of host immune and cell death responses associated with the influenza A virus PB1-F2 protein.
Transcriptomic analysis of host immune and cell death responses associated with the influenza A virus PB1-F2 protein.
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DOI：
10.1371/journal.ppat.1002202
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发表时间：
2011-08
期刊：
影响因子：
6.7
通讯作者：
Delmas B
中科院分区：
文献类型：
--
作者：
Le Goffic R;Leymarie O;Chevalier C;Rebours E;Da Costa B;Vidic J;Descamps D;Sallenave JM;Rauch M;Samson M;Delmas B
气道炎症在流感病毒的发病机制中起着重要作用，并可能导致致命的结果。流感研究领域具有挑战性的目标之一是确定与感染期间发生的免疫病理疾病相关的分子基础。虽然其在病毒周期中的确切功能尚不清楚，但病毒蛋白PB1-F2被认为在感染宿主内发挥有害活性。利用不能表达PB1-F2及其野生型同源物的工程重组病毒，我们在小鼠模型中分析和比较了这两种病毒的致病性和宿主反应。我们证实，PB1-F2的缺失使病毒的毒性降低。受感染肺部的全球转录组学分析揭示了PB1-F2对宿主产生的应答的强大影响。因此，在感染两天后，PB1-F2失效严重减少了宿主激活的基因数量。PB1-F2的表达诱导了与细胞死亡、炎症反应和中性粒细胞趋化性相关的活化基因的数量和表达水平的增加。当生成PB1-F2特异性的相互作用基因网络时，我们发现IFN-γ是PB1-F2调节基因的中心调节因子。凋亡实验证实了气道募集的白细胞的细胞死亡增强，证实了PB1-F2的促凋亡特性。使用NF-kB荧光素酶腺病毒载体，我们能够在体内量化NF-kB在流感病毒感染介导的炎症中的作用；我们发现PB1-F2的表达增强了NF-kB的活性。最后，我们量化了气道内的中性粒细胞募集，并表明这种类型的白细胞在野生型病毒感染期间更为丰富。总之，这些数据表明，在IAV感染期间，PB1-F2强烈影响宿主的早期反应，并为PB1-F2介导毒力的机制提供了新的见解。甲型流感病毒可引起严重的呼吸道疾病。2001年发现的一种病毒蛋白PB1-F2被怀疑在流感相关肺炎中发挥作用。为了了解PB1-F2在甲型流感病毒感染发病机制中的作用，我们设计了一种不能表达PB1-F2的突变病毒。通过高通量基因表达试验，我们比较了野生型感染和突变型感染小鼠的宿主反应。我们发现PB1-F2的表达增强了小鼠的免疫细胞死亡和炎症反应。由PB1-F2表达介导的炎症反应导致空气空间内白细胞的大量募集，这是流感介导的免疫病理的特征。我们的研究结果表明，PB1-F2是一种毒力因子，参与了急性流感病毒肺炎中炎症反应的解除。这些数据揭示了病毒与宿主相互作用的复杂性，并帮助我们了解流感病毒介导严重呼吸道疾病的机制。
Airway inflammation plays a major role in the pathogenesis of influenza viruses and can lead to a fatal outcome. One of the challenging objectives in the field of influenza research is the identification of the molecular bases associated to the immunopathological disorders developed during infection. While its precise function in the virus cycle is still unclear, the viral protein PB1-F2 is proposed to exert a deleterious activity within the infected host. Using an engineered recombinant virus unable to express PB1-F2 and its wild-type homolog, we analyzed and compared the pathogenicity and host response developed by the two viruses in a mouse model. We confirmed that the deletion of PB1-F2 renders the virus less virulent. The global transcriptomic analyses of the infected lungs revealed a potent impact of PB1-F2 on the response developed by the host. Thus, after two days post-infection, PB1-F2 invalidation severely decreased the number of genes activated by the host. PB1-F2 expression induced an increase in the number and level of expression of activated genes linked to cell death, inflammatory response and neutrophil chemotaxis. When generating interactive gene networks specific to PB1-F2, we identified IFN-γ as a central regulator of PB1-F2-regulated genes. The enhanced cell death of airway-recruited leukocytes was evidenced using an apoptosis assay, confirming the pro-apoptotic properties of PB1-F2. Using a NF-kB luciferase adenoviral vector, we were able to quantify in vivo the implication of NF-kB in the inflammation mediated by the influenza virus infection; we found that PB1-F2 expression intensifies the NF-kB activity. Finally, we quantified the neutrophil recruitment within the airways, and showed that this type of leukocyte is more abundant during the infection of the wild-type virus. Collectively, these data demonstrate that PB1-F2 strongly influences the early host response during IAV infection and provides new insights into the mechanisms by which PB1-F2 mediates virulence. Influenza A viruses may cause severe respiratory disease. PB1-F2, a viral protein identified in 2001 is suspected to play a role in influenza-related pneumonia. In order to understand the impact of PB1-F2 in the pathogenesis underlying Influenza A virus infection, we engineered a mutant virus unable to express PB1-F2. By the use of high-throughput gene expression assays, we compared the host responses of the wild-type-infected and the PB1-F2 mutant-infected mice. We identified that PB1-F2 expression enhances the immune cell death and inflammatory responses of mice. The inflammatory response mediated by the PB1-F2 expression leads to a massive recruitment of leukocytes within the air spaces, a feature that characterizes the influenza-mediated immunopathology. Our results suggest that PB1-F2 is a virulence factor implicated in the deregulation of the inflammatory response observed in acute influenza virus pneumonia. These data underlie the complexities of virus-host interactions and help us understand by which mechanisms Influenza viruses mediate severe respiratory diseases.
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Toll样受体（TLR）3对病毒诱导的急性肺炎的有害贡献。
影响因子：
6.7
作者：
Le Goffic, Ronan;Balloy, Viviane;Lagranderie, Micheline;Alexopoulou, Lena;Escriou, Nicolas;Flavell, Richard;Chignard, Michel;Si-Tahar, Mustapha
通讯作者：
Si-Tahar, Mustapha
高度致病的H5N1禽流感病毒的PB1-F2中的三种氨基酸变化会影响野鸭的致病性。
影响因子：
2.7
作者：
Marjuki, Henju;Scholtissek, Christoph;Franks, John;Negovetich, Nicholas J.;Aldridge, Jerry R.;Salomon, Rachelle;Finkelstein, David;Webster, Robert G.
通讯作者：
Webster, Robert G.
影响因子：
6.4
作者：
Iverson, Amy R.;Boyd, Kelli L.;McCullers, Jonathan A.
通讯作者：
McCullers, Jonathan A.
影响因子：
5
作者：
Kash, John C.;Goodman, Alan G.;Katze, Michael G.
通讯作者：
Katze, Michael G.
DOI：
10.1016/s1386-6532(03)00122-7
发表时间：
2004-03
期刊：
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
影响因子：
--
作者：
Ward CL;Dempsey MH;Ring CJ;Kempson RE;Zhang L;Gor D;Snowden BW;Tisdale M
通讯作者：
Tisdale M