Detection of Mammalian Virulence Determinants in Highly Pathogenic Avian Influenza H5N1 Viruses: Multivariate Analysis of Published Data
Detection of Mammalian Virulence Determinants in Highly Pathogenic Avian Influenza H5N1 Viruses: Multivariate Analysis of Published Data
复制标题
DOI：
10.1128/jvi.00608-09
复制
发表时间：
2009-10-01
影响因子：
5.4
通讯作者：
Brown, A. J. Leigh
中科院分区：
文献类型：
--
作者：
Lycett, S. J.;Ward, M. J.;Brown, A. J. Leigh
高致病性禽流感 (HPAI) 病毒 H5N1 会感染水禽和陆禽，并可感染包括人类在内的哺乳动物并导致死亡。然而，HPAI H5N1 菌株对哺乳动物的毒性并不相同，并且一些菌株已被证明在实验感染中仅引起轻微症状。由于大多数关于哺乳动物毒力基础的实验研究规模较小，因此我们对现有实验研究进行了荟萃分析，并使用贝叶斯图形模型（BGM）来提高推理能力。我们应用文本挖掘技术来识别 27 项单独的研究，这些研究通过实验确定了包含 69 个完整基因组序列的 HPAI H5N1 菌株的致病性。所有 11 个基因的氨基酸序列数据均被编码为二进制数据，用于表示是否存在与哺乳动物毒力相关的突变或非共有残基。在该数据集中检查了先前涉及毒力决定因素的位点与哺乳动物毒力的关联，并选择具有最显着关联的位点进行进一步的 BGM 分析。分析表明，哺乳动物的毒力是一种复杂的遗传性状，直接受聚合酶碱性 1 (PB1) 和 PB2、非结构 1 (NS1) 和血凝素 (HA) 基因突变的影响。还发现了一些片段内和片段间的相关性，我们假设可能存在两种独立的毒力机制，涉及聚合酶和 NS1 突变或 NS1 和 HA 突变的特定组合。
Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.