A COMPREHENSIVE RESOURCE FOR HIGH-THROUGHPUT PROFILING OF WORM AND ZEBRAFISH METABOLOMES

Project Summary Coronavirus disease 2019, also known as COVID-19, has created an unprecedented global health crisis.Thus far, the only strategy to minimize spread of the virus has been physical distancing. Unfortunately, theseefforts are negatively impacting the psychiatric health of the nation and devastating our economy. It is thereforeimperative that a treatment for COVID-19 be developed expeditiously. Worms (Caenorhabditis elegans) and zebrafish (Danio rerio) are premier model organisms that havehistorically provided profound insight into a number of human diseases. At this time, however, the applicationof worms and zebrafish to COVID-19 has been severely limited. Currently, the major issue is that there are noreported models in these animals to capture the complex pathophysiology of COVID-19. The overarchingobjective of the current proposal is to create a resource that will help bridge this gap. Specifically, we aim tofacilitate the application of metabolomics to COVID-19 related studies in worms and zebrafish. The basis of our work will be metabolomic analysis of human patients with COVID-19. In addition tocomparing patients with mild and severe disease, samples from an infected patient will be compared tosamples from the same patient after recovery. Together, we expect these experiments to provide acomprehensive picture of metabolic pathways that are altered during COVID-19 pathology. We will then map the metabolic dysfunction we uncover in patients to the worm and zebrafish metabolomesby using technologies that we have developed in the parent award. The result will be a resource delineating acomprehensive set of reference COVID-19 pathways in worms and in zebrafish. This will empower the use ofworms and zebrafish to answer important COVID-19 questions, two examples of which we propose to pursuehere. Our first question is: what is the mode of action of small-molecule drugs in clinical trials to treat COVID-19 patients (e.g., hydroxychloroquine)? We will perform dose-response metabolomics on zebrafish exposed to20 small-molecule drugs currently in clinical trials to treat COVID-19. A comparison of each drug's target toreference COVID-19 pathways will provide insight into mode of action, off-target toxicity, and potentially assistin the improved design of new drugs. Our second question is: which disease processes contribute to COVID-19 pathology? We will perform metabolomics on zebrafish models of cytokine storm, respiratory distress, andorgan failure. Comparing metabolic changes from each of these models to reference COVID-19 pathways willimprove our understanding of which disease processes contribute to COVID-19 pathology. We note that the drugs and disease processes that we propose to evaluate here are largely incomplete,with many additional drugs and C. elegans disease models available to test. These opportunities, and manyothers, represent exciting future applications of our resource to advance our understanding of COVID-19through the use of model animals.