Post infectious fatigue and circadian rhythm disruption in long-COVID and other infections: a need for further research.

Chronic fatigue syndrome (CFS) remains a subject of scientific research specifically with regards to its association with infections, including the more recently described Long COVID condition. Chronic fatigue and sleep disturbances in Long COVID are intricately linked to disruptions in circadian rhythms, driven by distinct molecular and cellular mechanisms triggered by SARS-CoV-2 infection. This can be driven by various mechanisms including dysregulation of key clock genes (CLOCK, BMAL1, PER2), mitochondrial dysfunction impairing oxidative phosphorylation, and cytokine-induced neuroinflammation (e.g., interleukin-6, tumor necrosis factor-alpha). Epigenetic changes, including DNA methylation at clock-related loci, particularly in peripheral tissues, further contribute to systemic circadian dysregulation. This work underscores the multifaceted molecular and systemic disruptions to circadian regulation in relation to fatigue and sleep disturbances identified as post-infectious sequelae, focusing on the Long COVID condition.