Long Covid is a disabling post-viral disease state that impacts over 400 million people worldwide, with no effective treatment currently available. Despite incomplete mechanistic understanding, lack of clinically actionable biomarkers, and insufficient policymaker recognition, significant progress has been made in recent years, revealing a clear histological and pathophysiological basis for the condition. SARS-CoV-2 infection prompts a complex immune response involving both innate and adaptive responses and immunothrombosis mechanisms. The virus infects multiple cell types and tissues, primarily those expressing ACE-2, including enterocytes, cardiomyocytes, and vasculature. Tissues with lower ACE-2 expression, like the brain, might be affected indirectly via immune-mediated and microthrombotic events. ACE-2 expression varies with disease severity and immune activation, including macrophage infiltration and microthrombi. Following acute infection, viral antigens may persist in tissues for years, continuously modulating the immune system, although they are inconsistently found in plasma. Acute systemic tissue injury releases host cell antigens which trigger autoimmunity. Enterocyte infection, inflammation, and antibiotic therapy during early Covid-19 cause gut microbial dysbiosis, which parallels the disease course. Microvascular damage and thrombosis result from endothelial damage, platelet infection, and activation of complement and coagulation cascades, leading to tissular hypoxemia, apoptosis, necrosis, and organ dysfunction. Mitochondrial respiratory chain changes and altered glucose and tryptophan metabolism worsen tissue damage, contributing to exercise intolerance and muscle necrosis post-exercise. All these and additional factors, like cranial nerve, suprarenal, or pancreatic dysfunction, contribute to long Covid’s diverse clinical presentation. Host tissue susceptibility, predisposition, and functional reserve, but also stochastic phenomena, influence individual clinical presentations. Long Covid affects individuals with over 150 potential symptoms impacting various organs and systems, often with a remitting-relapsing course. However, 10 to 15 core symptoms help identify symptom clusters, aiding targeted mechanistic studies and clinical trials. Despite its complexity, Long Covid is being understood at a pace never seen before. The recent NIH Recover-TLC initiative represents a unique opportunity to advance towards finding a cure for this disease.
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