SUMMARY Our overarching hypothesis is that the pathogenesis of ME/CFS entails gene-environment interactions between the immune system and infectious agents. Many individuals with ME/CFS have a prodrome consistent with systemic infection. Although there are instances where disease is clearly linked to infection, no agent or agents have been consistently implicated. The strategic plan for the second cycle of the Center reflects insights we and others have gained into the pathogenesis of ME/CFS and other disorders, including Post Acute Sequelae of COVID-19 (PASC), and the evolution of experimental methods since the initiation of our Center. It includes three complementary projects: Project 1, Molecular Correlates of Symptom Severity in ME/CFS, leverages advances in technology to create a smart phone app to track the course of illness and correlate with biological manifestations. Project 2, Genotypic Analysis in ME/CFS, builds on the UK-based Decode ME project, investments by the research advocacy organization Solve ME in identifying ME/CFS cases in the US, and the investments made in genotyping 400,000 control subjects in the Kaiser Permanente Research Bank (KPRB) to identify genotypic differences using Genome Wide Association Studies (GWAS) in the US. Project 3, Pathogen Discovery through Longitudinal Serological Surveillance in ME/CFS, will search for evidence of exposure to infectious agents prior to and after ME/CFS diagnosis, using the unique resource of the Department of Defense Serum Repository and a new phage display method based on short peptides, that provides the granularity required to differentiate exposure to different viral agents as well as to differentiate acute, persistent, re-activated infections.

NARRATIVE The Center for Solutions for ME/CFS is dedicated to advancing the science of ME/CFS and advocating for the ME/CFS community through research that focuses on identifying genetic and environmental factors that contribute to disease and finding biomarkers that enable diagnosis and clinical management. In this second cycle of the Center, we will pursue complementary projects that examine samples collected in temporal proximity to variation in disease severity and prospectively, prior to diagnosis. We will test for antibody evidence of infections that may trigger initiation or exacerbation of symptoms; measure levels of small molecules in blood, saliva, and feces for clues to dysfunction at the cellular level, and sequence the genomes of people with ME/CFS to look for factors that influence risk for disease.