From infection to chronic fatigue: systems biology of ME/CFS, long COVID, and post-viral syndromes

This Research Topic is part of a series with Fatigue: Physiology and Pathology and Exploring Chronic Fatigue: Neural Correlates, Mechanisms, and Therapeutic Strategies.Fatigue—spanning physical, cognitive, and systemic domains—remains one of the most elusive and clinically impactful phenomena in medicine. While prior volumes in this series have addressed fatigue from neural and physiological perspectives, a critical frontier lies in understanding how acute infections transition into chronic, disabling conditions. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Long COVID (PASC), and related post-viral syndromes converge on a shared and defining feature: persistent, activity-limiting fatigue often accompanied by post-exertional malaise (PEM).This Research Topic positions chronic fatigue not merely as a symptom, but as an emergent property of multi-system dysregulation. Increasing evidence suggests that the progression from acute infection to chronic illness involves interconnected disturbances across immune signaling, autonomic regulation, neuroinflammatory pathways, and cellular energy metabolism. These processes may be sustained by factors such as viral antigen persistence, maladaptive immune responses, endothelial dysfunction, and impaired bioenergetics. Rather than acting in isolation, these mechanisms likely form dynamic feedback loops that perpetuate symptom chronicity.The gut microbiome and its metabolomic outputs represent one layer within this broader systems framework. Microbial dysbiosis, altered short-chain fatty acids, and immune–microbiota interactions may influence host metabolism, barrier integrity, and neuroimmune communication. However, microbiome alterations must be interpreted within the context of host physiology, including mitochondrial function, autonomic balance, and systemic inflammation.This collection aims to advance an integrative, cross-disciplinary understanding of post-infectious fatigue by bringing together research spanning immunology, neuroscience, metabolism, vascular biology, and computational modeling. We particularly encourage approaches that move beyond single-system explanations toward identifying mechanistic links and clinically meaningful endotypes. Contributions that incorporate longitudinal designs, deep phenotyping, and multi-omics integration are especially welcome.By reframing chronic fatigue as a systems-level outcome of interacting biological networks, this Research Topic seeks to support the development of objective biomarkers, mechanistically grounded diagnostics, and targeted therapeutic strategies across ME/CFS, Long COVID, and related conditions.Suggested topics include:• Systems-level models of post-infectious fatigue integrating immune, autonomic, and metabolic networks.• Longitudinal trajectories from acute infection to chronic illness, including early predictors of non-recovery.• Bioenergetic dysfunction and metabolic inflexibility, including mitochondrial, redox, and substrate utilization abnormalities.• Neurovascular and endothelial mechanisms, including cerebral blood flow regulation and oxygen delivery impairments.• Autonomic regulation and cardiorespiratory coupling, including orthostatic intolerance and altered hemodynamics during exertion.• Neuroimmune interactions and central fatigue, including glial activation and brain–body signaling pathways.• Multi-omics and machine learning approaches for patient stratification and endotype discovery.• Host–microbiome–metabolome interactions in the context of systemic energy regulation and inflammation.• Sex-specific, hormonal, and genetic modifiers of susceptibility and disease expression.• Objective measurement of post-exertional malaise using physiological, metabolic, or digital biomarkers.• Translational frameworks linking mechanistic findings to therapeutic targets.• Interventional studies targeting bioenergetics, autonomic function, immune modulation, or vascular health. Topic editors: Sławomir Kujawski, Pawel Zalewski, Karl MORTEN, Lynette Hodges Source: https://www.frontiersin.org/research-topics/82413/from-infection-to-chronic-fatigue-systems-biology-of-mecfs-long-covid-and-post-viral-syndromes