CHRONIC INFLAMMATION AND LONG COVID: ONGOING STUDIES INTO THE PROINFLAMMATORY AND IMMUNE EXHAUSTION PATHWAYS ACTIVATED DURING LONG-TERM POST VIRAL CONDITIONS

Abstract

Long-term COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) as a chronic multisystem disorder with neuroinflammation, endothelial dysfunction, metabolic dysfunction, and sustained immunological dysregulation after initial infection is becoming more recognized. More and more evidence is beginning to indicate that the continued activation of the pro-inflammatory and immunological exhaustion mechanisms and the inability to resolve inflammation play a significant role in disease persistence. This review is a summary of mechanistic research of cytokine dysregulation, NF--KB and JAK-STAT activation, inflammasome signalling, T-cell fatigue, myeloid cell reprogramming, viral persistence, autoimmunity, mitochondrial dysfunction, and microvascular damage in Long COVID. Findings are put in perspective by providing comparative data of various post-viral illnesses. The existing immunomodulatory clinical trials and biomarker opportunities are assessed on a global basis. The evidence all points towards a multifactorial mechanism involving the combination of the ongoing antigenic stimulation, maladaptive immune resolution and endothelial-metabolic dysfunction to sustain chronic inflammation. The dual relationship between these pathways determines the need to comprehend them to make a difference in post-viral disease therapy stratification and precision medicine.