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

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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.