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

了解为什么感染会导致疾病，以及疾病的病理学如何随组织部位、感染后时间和宿主物种而变化，是微生物-宿主相互作用中心的关键问题。为了回答这个问题，本提案比较了禽流感病毒与自然鸭宿主（通常在感染后保持无症状）之间的相互作用，以及与意外家禽宿主（出现严重症状）之间的相互作用。该提案是分析化学家，病毒学家和兽医病理学家之间的高度集成的跨学科合作。该团队将使用最先进的空间代谢组学方法来绘制与这些宿主的允许和非允许组织的感染相关的代谢变化，它们在感染和恢复过程中的轨迹，以及它们与新病毒序列出现的关联。总的来说，该项目将导致对代谢，疾病和感染结果之间的空间交叉的重大见解。了解这些交叉点将揭示病毒如何在对食物重要的宿主动物（家禽）中引起疾病，并且可能是确定治疗方法或其他策略的关键，这些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的主要利益攸关方进行外联。成人教育活动和代表性不足的年轻科学家和有抱负的研究人员的培训也将发生，以帮助我们的国家准备领导人的生物经济。感染生物学的一个基本问题是了解导致致病性与非致病性结果的因素，以及这些如何随着空间和时间的推移以及宿主之间的演变。自然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。该提案利用禽流感病毒的自然宿主与偶然宿主，解决了感染生物学中的这一关键空白。待检验的中心假设是，组织将呈现微小的代谢变化，并在自然宿主中呈现朝向恢复的代谢轨迹，而代谢改变在意外宿主中将更严重和持久。我们还假设组织和意外宿主与自然宿主之间代谢物可用性的差异为在意外宿主中选择更具毒性的菌株提供了环境。为了验证这些假设，我们将结合联合收割机实验性流感病毒感染的自然和意外的主机与液相色谱-质谱为基础的空间代谢组学和下一代测序（NGS）。总的来说，我们将产生一个全面的，系统级的，空间和时间上解决的见解之间的相互作用，天然鸟类宿主，病毒宿主细胞代谢途径，并在一系列感染结果的流感易感性。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的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.