Inflammation-, immunothrombosis,- and autoimmune-feedback loops may lead to persistent neutrophil self-stimulation in long COVID.

Abstract

Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.