Immunogenetic regulation of organ crosstalk in long COVID

Long COVID represents a heterogeneous, multisystem condition arising from the incomplete resolution of acute SARS-CoV-2 infection. Rather than an organ-restricted disorder, accumulating evidence indicates that long COVID is driven by persistent immune dysregulation shaped by immunogenetic susceptibility, endothelial injury, and pathological organ crosstalk. Current understanding of the genetic variables linked to viral entry, autoimmunity, cytokine imbalance, and interferon signalling abnormalities that cause tissue dysfunction and chronic inflammation is limited. Immunothrombosis and endothelial dysfunction are key processes that connect immunological activation to microvascular damage and compromised tissue perfusion. A comprehensive systems biology framework examines organ-specific symptoms across the neurological, gastrointestinal, renal, metabolic, and cardiopulmonary systems. We also note that two important causes of fatigue and exercise intolerance are mitochondrial dysfunction and metabolic reprogramming. We conclude by outlining multi-omics integration and biomarker discovery, emphasising the necessity of interdisciplinary approaches to improve long-term outcomes in long COVID.