OSIB: Metabolic cartography of influenza A virus infection and host-pathogen interaction in the natural and accidental host

OSIB：自然和意外宿主中甲型流感病毒感染和宿主-病原体相互作用的代谢制图

• 批准号: 2318557
• 负责人: Laura-Isobel McCall
• 金额: $ 82.62万
• 依托单位: University of Oklahoma Norman Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2318557&HistoricalAwards=false
• 关键词: OSIB; Metabolic; cartography; influenza; virus; OSIB; Metabolic; cartography; influenza; virus

Understanding why an infection leads to disease, and how pathology of disease changes over tissue site, time post-infection, and host species are critical questions at the center of microbe-host interactions. To answer this question, this proposal compares the interaction between avian influenza virus and natural duck hosts who usually remain asymptomatic following infection, versus infection with accidental poultry hosts, who present with severe symptoms. This proposal is a highly integrated interdisciplinary collaboration between analytical chemists, virologists, and veterinary pathologists. This team will use a state-of-the-art spatial metabolomics approach to map the metabolic changes associated with infection across permissive and non-permissive tissues of these hosts, their trajectories over infection and recovery, and their association with emergence of new virus sequences. Overall, this project will lead to major insight into the spatial intersection between metabolism, disease and infection outcomes. Understanding these intersections will reveal how viruses can cause disease in host animals important for food (poultry) and may be key in identifying therapeutics or other strategies that can benefit animals important to the food chain and humans. Broader impacts include outreach to the poultry and agriculture industry, major stakeholders in bird health for wildlife and food sources. Adult education events and training of under-represented young scientists and aspiring researchers will also occur to help our country prepare leaders for the bioeconomy.A fundamental question in infection biology is to understand the factors that lead to pathogenic vs non-pathogenic outcomes, and how these evolve over space and time, and between hosts. Infection in natural reservoir hosts may lead to subclinical or mild disease, while infection of other “accidental” hosts will lead to severe illness. This proposal addresses this critical gap in infection biology, using natural vs accidental host of avian influenza virus. The central hypothesis to be tested is that tissues will present minor metabolic changes and a metabolic trajectory towards recovery in natural hosts, while metabolic alterations will be more severe and persistent in accidental hosts. We also hypothesize that differential metabolite availability between tissues and accidental vs natural hosts provides an environment for the selection of more virulent strains in accidental hosts. To test these hypotheses, we will combine experimental influenza virus infection in natural and accidental hosts with liquid chromatography-mass spectrometry based spatial metabolomics and next generation sequencing (NGS). Overall, we will generate a comprehensive, systems-level, spatially and temporally resolved insights into the interaction between natural avian hosts, virus-host cell metabolic pathways, and susceptibility to influenza across a range of infection outcomes. This project is jointly funded by the Symbiosis, Infection and Immunity Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

了解为什么感染会导致疾病，以及疾病的病理如何在组织部位，感染后和宿主物种变化是微生物宿主相互作用的中心的关键问题。为了回答这个问题，该提案比较了通常在感染后通常保持不对称的天然鸭病毒与天然鸭宿主之间的相互作用，而感染了意外的家禽宿主，后者出现严重的症状。该建议是分析化学家，病毒学家和兽医病理学家之间高度综合的跨学科合作。该团队将使用最先进的空间代谢组学方法来绘制这些宿主的允许和非耐受性tisues感染相关的代谢变化，他们对感染和恢复的轨迹以及与新病毒序列的出现相关性。总体而言，该项目将导致对代谢，疾病和感染结果之间的空间交集的重大见解。了解这些交叉路口将揭示病毒如何引起对食物（家禽）重要的宿主动物疾病，并且可能是识别可以使对食物链和人类重要的动物受益的疗法或其他策略的关键。更广泛的影响包括对家禽和农业行业的宣传，野生动植物和食物来源的鸟类健康的主要利益相关者。成人教育事件和人为不足的年轻科学家和有抱负的研究人员的培训也将有助于我们国家为领导者做好生物经济的准备。感染生物学的基本问题是了解导致致病性与非致病性结果的因素，以及这些因素如何在空间和时间之间以及主机之间的演变。天然储层宿主的感染可能导致亚临床或轻度疾病，而其他“意外”宿主的感染将导致严重疾病。该提案使用自然与偶然的鸟类影响病毒的偶然宿主来解决感染生物学中的这一关键差距。要测试的中心假设是，组织将出现较小的代谢变化，并具有针对自然宿主恢复的代谢轨迹，而在意外宿主中，代谢改变将更加严重和持续。我们还假设组织与意外宿主之间的差异代谢物可用性为选择在意外宿主中选择更多病毒菌株的环境提供了环境。为了检验这些假设，我们将将自然和意外宿主的实验影响病毒感染与基于液相色谱 - 质谱法的空间代谢组学和下一代测序（NGS）相结合。总体而言，我们将在天然鸟类宿主，病毒宿主宿主的细胞代谢途径以及影响一系列感染结果的影响方面产生全面的，系统级，空间和临时的见解。该项目由共生，感染和免疫计划以及刺激竞争研究的既定计划（EPSCOR）共同资助。该奖项反映了NSF的法定任务，并通过使用基金会的智力优点和更广泛的影响来审查标准，认为通过评估来获得珍贵的支持。