Project Abstract Every year over 1 million American adults and children develop overwhelming infection leading to a rotting of their body we call ‘sepsis’, and death in up to 1 of 4 afflicted. We and others have asked the question “why do patients continue to die of organ shutdown?” In the previous funding period we used clinical information and samples already obtained in our R01 funded audit of 401 children with sepsis and took advantage of the wonderful advances made this millenia in computer technology, big data, bioinformatics, and the study of human and virus genetics to understand how too much inflammation and too little immune response lead to organ shutdown. First, we used ‘Watson’ like machine learning at 24 hours to identify a sub-group of children we named PedSep-D who subsequently go on to death with organ shutdown caused by too much inflammation and clotting that we can now reverse with anti-inflammatory and anti-thrombotic therapies. Second, we used an ‘Ancestry.com’-like or ‘23 and me’-like next generation sequencing approach to identify genes in individual children that were related to too much inflammation and too little ability to kill infection which we can now treat on an individual basis using ‘precision medicine’ therapies. Third, we used molecular biology testing approaches to identify Latent Epstein Barr Virus infection as an asymptomatic preexisting high- risk condition that is associated with death when children develop sepsis. Disordered inflammation and immunity are closely related to altered metabolism. We previously linked all three to organ shutdown and death in pediatric sepsis. In the next funding period we will investigate toxic ‘metabolism’ as a cause of organ shutdown by measuring plasma metabolomics in these same 401 child samples. In Specific Aim 1 we test the hypothesis that PedSep D patients have a shift to aerobic glycolysis that drives toxic macrophage activation that can potentially be reversed with glucose restriction and / or Metformin treatment. In Specific Aim 2 we test the hypothesis that gene variants related to Inborn Errors of Metabolism contribute to organ shutdown that can be reversed using established Precision Medicine metabolic therapies. In Specific Aim 3 we test the hypothesis that Epstein Barr Virus latent infection is causally associated with organ shutdown because it induces Immuno-Metabolic reprogramming of the host response in sepsis towards aerobic glycolysis that is potentially reversed with repurposed drugs such as Metformin. We also examine methylation epigenetics in these children to begin to understand the molecular basis for this host pathogen response. Our long-term objective is to plan ‘precision’ medicine and ‘individualized’ medicine clinical trials testing therapies that address Inflammation-Immune-Metabolism dysregulation on an individual patient basis in order to further reduce death from sepsis induced organ shutdown in children.