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: 2344946
• 负责人: Laura-Isobel McCall
• 金额: $ 82.62万
• 依托单位: San Diego State University Foundation
• 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: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2344946&HistoricalAwards=false
• 关键词: 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.

了解感染导致疾病的原因，以及疾病的病理如何随着组织部位、感染后的时间和宿主物种的变化而变化，是微生物与宿主相互作用的中心问题。为了回答这个问题，这项建议比较了禽流感病毒和感染后通常保持无症状的自然鸭子宿主与出现严重症状的意外家禽宿主之间的相互作用。这项建议是分析化学家、病毒学家和兽医病理学家之间高度整合的跨学科合作。该团队将使用最先进的空间代谢组学方法，绘制与感染有关的代谢变化，跨越这些宿主的许可和非许可组织，它们在感染和恢复方面的轨迹，以及它们与新病毒序列出现的关联。总体而言，该项目将导致对新陈代谢、疾病和感染结果之间的空间交集的重大洞察。了解这些交叉将揭示病毒如何在对食物(家禽)重要的宿主动物中引起疾病，并可能是确定治疗方法或其他策略的关键，这些疗法或其他策略可以使对食物链和人类重要的动物受益。更广泛的影响包括与家禽和农业、野生动物和食物来源的鸟类健康方面的主要利益攸关方进行接触。还将举办成人教育活动和对未被充分代表的年轻科学家和有抱负的研究人员进行培训，以帮助我国为生物经济学培养领导者。感染生物学的一个基本问题是了解导致致病和非致病结果的因素，以及这些因素如何在空间和时间以及宿主之间进化。自然宿主的感染可能会导致亚临床或轻度疾病，而其他“意外”宿主的感染会导致严重的疾病。这项建议利用禽流感病毒的自然宿主和意外宿主，解决了感染生物学中的这一关键差距。需要检验的中心假设是，在自然宿主中，组织会出现轻微的代谢变化，并呈现恢复的代谢轨迹，而在意外宿主中，代谢变化将更加严重和持久。我们还假设，组织和意外宿主与自然宿主之间的代谢物可用性差异为意外宿主选择毒力更强的菌株提供了环境。为了验证这些假设，我们将结合实验流感病毒在自然和意外宿主中的感染，以及基于液-质联用的空间代谢组学和下一代测序(NGS)。总体而言，我们将对自然禽类宿主之间的相互作用、病毒-宿主细胞代谢途径以及一系列感染结果的流感易感性产生全面的、系统水平的、空间和时间分辨率的见解。该项目由共生、感染和免疫计划和既定的激励竞争性研究计划(EPSCoR)共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。