An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.
An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.
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DOI：
10.1371/journal.ppat.1004856
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Kawaoka Y
中科院分区：
文献类型：
--
作者：
Shoemaker JE;Fukuyama S;Eisfeld AJ;Zhao D;Kawakami E;Sakabe S;Maemura T;Gorai T;Katsura H;Muramoto Y;Watanabe S;Watanabe T;Fuji K;Matsuoka Y;Kitano H;Kawaoka Y
流感病毒对公共卫生构成重大挑战，2009年流感大流行就是明证。高致病性流感病毒感染通常伴随着早期高水平的炎性细胞因子，一些研究表明，这可能以菌株依赖的方式受到调节。然而，对强毒性流感毒株诱导的炎症反应的复杂动力学的全面表征是缺乏的。在这里，我们将基因共表达和非线性回归分析应用于流感感染小鼠肺部的时间过程，微阵列数据建立宿主炎症反应的数学模型。我们发现炎症相关基因表达的动态是由一种超灵敏的机制调控的，在这种机制中，低水平的病毒诱导最小的基因表达，但一旦超过阈值病毒滴度，表达就会被强烈诱导。细胞因子分析证实了几种关键炎症细胞因子的产生，如白细胞介素6和单核细胞趋化蛋白1，表现出超敏感的行为。对调节炎症相关基因反应途径的系统探索表明，这种超敏感反应机制的分子起源位于调节STAT1磷酸化的toll样受体途径分支内。本研究首次提供了流感病毒在全肺中诱导炎症的超敏感机制的证据，并提供了不同病毒株如何诱导不同时间炎症反应谱的见解。本文所建立的方法将有助于构建其他传染病的基因调控模型。疫苗足以保护公众健康免受季节性流感病毒的侵害，但当出现疫苗无法提供保护的意外毒株时，就需要其他治疗方法。在这项工作中，我们使用流感感染小鼠的基因表达和病毒生长数据来确定中度和致命流感病毒如何引发独特的炎症反应以及这些反应在疾病病理学中的作用。我们发现，所有测试的病毒生长和炎症反应之间的关系都可以通过超敏感反应来表征，在超敏感反应中，炎症反应被控制，直到病毒在肺部超过阈值浓度，之后发生强烈的炎症基因表达和细胞因子产生。这一发现挑战了致命流感病毒引发独特细胞因子和炎症反应的观念，并提供了额外的证据，证明病理是由病毒载量调节的，尽管是以高度非线性的方式。这些发现表明，免疫调节治疗可以专注于改变炎症反应动力学，以改善疾病病理。
Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases. Vaccines suffice for protecting public health against seasonal influenza viruses, but when unexpected strains appear against which the vaccine does not confer protection, alternative treatments are necessary. In this work, we used gene expression and virus growth data from influenza-infected mice to determine how moderate and deadly influenza viruses may invoke unique inflammatory responses and the role these responses play in disease pathology. We found that the relationship between virus growth and the inflammatory response for all viruses tested can be characterized by ultrasensitive response in which the inflammatory response is gated until a threshold concentration of virus is exceeded in the lung after which strong inflammatory gene expression and cytokine production occurs. This finding challenges the notion that deadly influenza viruses invoke unique cytokine and inflammatory responses and provides additional evidence that pathology is regulated by virus load, albeit in a highly nonlinear fashion. These findings suggests immunomodulatory treatments could focus on altering inflammatory response dynamics to improve disease pathology.
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