Quantifying the genetic and environmental factors driving avian influenza spillover

项目总结 过去的流感跨物种传播事件曾导致毁灭性的人类大流行。H5N1是一种 禽流感病毒，自1997年以来引起反复的、高致病性的人类感染。人类 通常通过与活禽的互动感染H5N1，越来越多的证据表明H5N1的传播 家禽感染与人类感染密切相关。尽管如此，基因和环境因素 促进H5N1在家禽中的传播仍不清楚。一种占主导地位的假说是野生鸟类 新病毒进入家禽，人类通过家禽相互作用获得感染。然而，这一比率 野鸟和家禽之间的传播从未被估计过。尽管某些畜牧业 户外饲养和运送到大型活家禽市场等做法被认为会增强H5N1病毒 流通，这些畜牧业做法的相对贡献从来没有得到系统的 评估过了。最后，病毒学研究得出了与人类适应有关的突变目录。 在实验室和动物研究中，目前用于查询新出现的H5N1毒株并评估 大流行风险。然而，许多感染人类的H5N1病毒株缺乏已知的适应标志，而且它是 目前尚不清楚这些突变是否预示着本质上的溢出风险。在这项提案中，我将使用系统发育学 以及确定H5N1跨物种遗传和环境驱动因素的统计方法 通过3个具体目标进行传播。与我的导师和合作导师一起完成这些项目将 请允许我实现我的职业目标，即在K99阶段结束前过渡到独立教员的角色。 1.我将使用最近开发的结构化合并模型来估计H5N1的比率 野鸟、家禽和人类之间的传播。我假设跨物种传播 经常发生在野生鸟类和家禽之间，但只有一小部分血统长期循环。我 预计会在家禽中观察到持续的传播，但不会在人类中观察到。 2.我将使用系统发育和统计方法来确定环境和畜牧业 促进H5N1在家禽中长期传播的做法。我假设短期溢出事件 将与室外禽舍和水稻种植联系在一起。长期机构将相互关联 疫苗接种覆盖率低，并被引入大型家禽市场。 3.阐明跨物种传播的遗传和表型决定因素。我将结合 全基因组扫描和表型验证在确定禽流感遗传相关性方面的能力 溢出效应。我推测，易受人类感染的H5N1基因谱系将被富含突变 实验链接到主机交换。我预测我们的扫描将识别出导致人类改良的突变 受体结合，在哺乳动物细胞中增强复制，以及消除干扰素的产生。

PROJECT SUMMARY Past influenza cross-species transmission events have lead to devastating human pandemics. H5N1 is an avian influenza virus that has caused recurrent, high pathogenicity human infections since 1997. Humans usually acquire H5N1 through interaction with live birds, and mounting evidence suggests that H5N1 circulation in poultry is strongly linked to human infection. Despite this, the genetic and environmental factors that promote H5N1 circulation in poultry remain unknown. A predominant hypothesis is that wild birds seed new viruses into poultry, and humans acquire infection via poultry interaction. However, the rate of transmission between wild birds and poultry has never been estimated. Although certain husbandry practices like outdoor rearing and transport to large, live poultry markets are hypothesized to enhance H5N1 circulation, the relative contributions of these husbandry practices have never been systematically assessed. Finally, virologic studies have produced a catalogue of mutations associated with human adaptation in laboratory and animal studies, which are currently used to query emerging H5N1 strains and assess pandemic risk. However, many human-infecting H5N1 strains lack known markers of adaptation, and it is unclear whether these mutations predict spillover risk in nature. In this proposal, I will use phylogenetic and statistical methods to determine the genetic and environmental drivers of H5N1 cross-species transmission through 3 specific aims. Completion of these projects with my mentors and co-mentors will allow me to achieve my career goal of transitioning to an independent faculty role by the end of the K99 phase. 1. I will use a recently developed structured coalescent model to estimate the rate of H5N1 transmission between wild birds, poultry, and humans. I hypothesize that cross-species transmission occurs frequently between wild birds and poultry, but only a small subset of lineages circulate long-term. I expect to observe ongoing transmission in poultry, but not in humans. 2. I will use phylogenetic and statistical methods to determine the environmental and husbandry practices that promote long-term H5N1 circulation in poultry. I hypothesize that short-term spillover events will be associated with outdoor poultry housing and rice cropping. Long-term establishments will be correlated with poor vaccination coverage and introduction into a large poultry market. 3. Elucidate genetic and phenotypic determinants of cross-species transmission. I will combine the power of a genome-wide scan with phenotypic validation to identify the genetic correlates of avian influenza spillover. I hypothesize that H5N1 lineages that are prone to human spillover will be enriched for mutations experimentally linked to host switching. I predict that our scan will identify mutations that elicit improved human receptor binding, enhanced replication in mammalian cells, and abrogation of interferon production.