Quantifying the genetic and environmental factors driving avian influenza spillover

量化导致禽流感蔓延的遗传和环境因素

• 批准号: 10593468
• 负责人: Louise Hillier Moncla
• 金额: $ 3.36万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593468
• 关键词: Quantifying; genetic; environmental; factors; driving

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.

项目概要 过去的流感跨物种传播事件已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、高致病性的人类感染。人类 通常通过与活禽互动而获得 H5N1，越来越多的证据表明 H5N1 的传播 家禽中的感染与人类感染密切相关。尽管如此，遗传和环境因素 促进 H5N1 在家禽中传播仍未知。一个主要的假设是野生鸟类播种 新病毒进入家禽，人类通过家禽互动而受到感染。然而，率 野鸟和家禽之间的传播从未被估计过。虽然有一定的牧 假设户外饲养和运输到大型活家禽市场等做法会增强 H5N1 循环方面，这些畜牧方式的相对贡献从未被系统地研究过。 评估。最后，病毒学研究产生了与人类适应相关的突变目录 在实验室和动物研究中，目前用于查询新出现的 H5N1 病毒株并评估 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记，因此 尚不清楚这些突变是否可以预测自然界的溢出风险。在这个提案中，我将使用系统发育 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 让我能够实现在 K99 阶段结束时过渡到独立教师角色的职业目标。 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 野生鸟类和家禽之间经常发生这种情况，但只有一小部分谱系能够长期传播。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 将与户外家禽饲养和水稻种植相关。长期机构将相互关联 疫苗接种覆盖率低且进入大型家禽市场。 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的力量，以确定禽流感的遗传相关性 溢出。我假设易于人类溢出的 H5N1 谱系将因突变而丰富 实验上与主机切换相关。我预测我们的扫描将识别出引起人类改善的突变 受体结合，增强哺乳动物细胞的复制，并消除干扰素的产生。

项目成果

Acute SARS-CoV-2 infections harbor limited within-host diversity and transmit via tight transmission bottlenecks.

• DOI: 10.1371/journal.ppat.1009849
• 发表时间: 2021-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Braun KM;Moreno GK;Wagner C;Accola MA;Rehrauer WM;Baker DA;Koelle K;O'Connor DH;Bedford T;Friedrich TC;Moncla LH
• 通讯作者: Moncla LH