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Detection of Mammalian Virulence Determinants in Highly Pathogenic Avian Influenza H5N1 Viruses: Multivariate Analysis of Published Data▿ †

机译:高度致病性禽流感H5N1病毒中哺乳动物毒力决定因素的检测:已发表数据的多元分析▿

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摘要

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.
机译:高致病性禽流感(HPAI)病毒H5N1感染水禽和家禽,并且可以感染哺乳动物并导致其死亡,包括人类在内。但是,HPAI H5N1菌株在哺乳动物中的毒性不一样,并且已显示某些菌株在实验性感染中仅引起轻度症状。由于大多数关于哺乳动物毒力基础的实验研究规模较小,因此我们对可用的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。将所有11个基因的氨基酸序列数据编码为二进制数据,以表示是否存在与哺乳动物中毒力相关的突变或非共有残基。在此数据集中检查了以前与毒力决定因素有关的位点与哺乳动物中的毒力的关联,并选择了关联性最高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个复杂的遗传特征,直接受聚合酶碱性1(PB1)和PB2,非结构性1(NS1)和血凝素(HA)基因突变的影响。还发现了多个段内和段间相关性,我们推测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。

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