Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections--A Prospective Cohort Study.
Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections--A Prospective Cohort Study.
复制标题
DOI：
10.1371/journal.ppat.1004869
复制
发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Couch RB
中科院分区：
文献类型：
--
作者：
Zhai Y;Franco LM;Atmar RL;Quarles JM;Arden N;Bucasas KL;Wells JM;Niño D;Wang X;Zapata GE;Shaw CA;Belmont JW;Couch RB
为了更好地了解自然获得性急性呼吸道病毒感染的全身反应，我们在2009年和2010年前瞻性招募了1610名健康成人。其中，对142例受试者进行了随访，以详细评价急性病毒性呼吸道疾病。我们在7个时间点检测了外周血基因表达：入组、5次疾病访视和每年研究结束时。133人完成了所有研究访视，并获得了技术上足够的外周血微阵列基因表达数据。73例（55%）有流感病毒感染，64例为甲型流感，9例为B型流感。其余受试者有鼻病毒感染（N = 32）、其他病毒感染（N = 4）或未发现病毒因子（N = 24）。在两个季节之间重复的结果显示，干扰素途径和先天免疫基因显著上调。这种情况持续了2-4天。数据显示在第4天和第6天的恢复期，差异表达的转录物涉及细胞增殖和修复。到第21天，基因表达模式与基线（入组）无法区分。与其他病毒感染相比，流感病毒感染诱导了更高程度和更长持续时间的疾病共享表达特征。使用谱系和活化状态特异性转录本产生细胞组成评分，在疾病急性期检测到伴随NK细胞主要活化的B和T淋巴细胞抑制模式。这些数据还表明，感染后重组和加强了多个动态基因模块。最后，我们检查了感染前和感染后的抗流感抗体滴度，确定了新的基因表达相关性。人类血细胞的基因表达谱可能揭示宿主对阿里斯如流行性H1N1的反应的复杂动力学。然而，只有有限的数据可用于系统层面的自然获得的感染。为了了解宿主反应的分子基础和网络编排，我们在2009年秋季和2010年前瞻性招募了1610名健康成年人，随访了流感样疾病受试者（N = 133）3周，并检查了他们外周血基因表达的变化。我们发现了感染后6天内宿主反应的不同阶段，并确定了区分流感病毒和非流感病毒感染的基因。然后，我们将焦点从基因表达模式转移到基因共表达模式。我们检测到与调控网络的核心特征相关的基因模块，并发现流感反应基因的连接性大幅增加。最后，我们确定了一个分子特征，与抗体反应显着相关的pH 1 N1病毒。综上所述，我们的研究结果提供了深入了解宿主对流感病毒感染反应的分子机制，并为研究全球协调应对阿里斯提供了宝贵的基础。免疫反应的分子相关性提示了干预和改进疫苗的目标。
To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates. Gene expression profiling of human blood cells might uncover the complex dynamics of host response to ARIs such as pandemic H1N1. However, only limited data are available on the system level response to naturally acquired infections. To understand the molecular bases and network orchestration of host responses, we prospectively enrolled 1610 healthy adults in the fall of 2009 and 2010, followed the subjects with influenza-like illness (N = 133) for 3 weeks, and examined changes in their peripheral blood gene expression. We discovered distinct phases of the host response spanning 6 days after infection, and identified genes that differentiate influenza from non-influenza virus infection. We then moved the focus from gene expression patterns to gene co-expression patterns. We detected gene modules that are related to core features of regulatory networks and found a substantial increase in the connectivity of the influenza responsive genes. Finally, we identified a molecular signature that correlated significantly with antibody response to pH1N1 virus. Taken together, our findings offer insights into the molecular mechanisms underlying host response to influenza virus infection, and provide a valuable foundation for investigation of the global coordinated responses to ARIs. Molecular correlates of the immune response suggest targets for intervention and improved vaccines.
登录
查看更多内容
影响因子：
5.4
作者：
Ioannidis, Ioannis;McNally, Beth;Flano, Emilio
通讯作者：
Flano, Emilio
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
5.4
作者：
Chaussabel D;Pascual V;Banchereau J
通讯作者：
Banchereau J
影响因子：
39.2
作者：
DOUGLAS, RG;ALFORD, RH;COUCH, RB
通讯作者：
COUCH, RB
影响因子：
3.6
作者：
Bucasas, Kristine L.;Mian, Asad I.;Belmont, John W.
通讯作者：
Belmont, John W.