Quantifying the genetic and environmental factors driving avian influenza spillover

项目摘要 过去的流感跨物种传播事件导致了毁灭性的人类大流行。H5N1是一种 自1997年以来，禽流感病毒已引起反复的、高致病性的人类感染。人类 通常通过与活禽接触感染H5N1，越来越多的证据表明，H5N1的传播 禽流感与人类感染密切相关。尽管如此，遗传和环境因素， H5N1病毒在家禽中传播的可能性尚不清楚。一个主要的假设是， 新病毒进入家禽，人类通过家禽相互作用获得感染。然而， 野生鸟类和家禽之间的传播从未得到估计。虽然某些畜牧业 假设户外饲养和运输到大型活禽市场等做法会增强H5N1 流通，这些畜牧业实践的相对贡献从未被系统地 评估。最后，病毒学研究已经产生了一个与人类适应性相关的突变目录 在实验室和动物研究中，目前用于查询新出现的H5N1毒株， 流行病风险。然而，许多感染人类的H5N1毒株缺乏已知的适应性标记， 目前尚不清楚这些突变是否预示着自然界中的溢出风险。在这个建议中，我将使用系统发育 和统计方法，以确定H5N1跨物种的遗传和环境驱动因素 通过三个具体目标实现。完成这些项目与我的导师和共同导师将 让我实现我的职业目标过渡到一个独立的教师角色的K99阶段结束。 1.我将使用最近开发的结构化聚结模型来估计H5N1的速率 野生鸟类、家禽和人类之间的传播。我假设跨物种传播 在野生鸟类和家禽之间经常发生，但只有一小部分谱系长期流传。我 预计将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。我假设短期的溢出事件 将与户外家禽饲养和水稻种植有关。长期机构将与 疫苗接种覆盖率低，并引入大型家禽市场。 3.阐明跨物种传播的遗传和表型决定因素。我会把联合收割机 全基因组扫描与表型验证在确定禽流感遗传相关性方面的作用 溢出我假设，H5N1病毒的谱系，容易向人类传播，将丰富的突变 实验性地与宿主转换有关。我预测我们的扫描将识别出突变， 受体结合、哺乳动物细胞中增强的复制和干扰素产生的消除。

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.