Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients.

The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.

Is SARS-CoV-2 Spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors?

The innate immune cells play an important role in handling early infections, and can eliminate them completely up to a certain threshold. Beyond that threshold they take up their role in "The Resolution of Inflammation". The recognition of the SARS-CoV-2 antigen triggers an eicosanoid storm and initiates a robust inflammatory response. This establishes a positive feedback loop which develops into a sustained cytokine storm which interferes with the activation of adaptive immune cells. The mechanism of this interaction, and hence the pathogenesis of the virus with the immune system, is yet to be determined. In silico studies predict a direct SARS-CoV-2 spike glycoprotein interaction with nicotinic acetylcholine receptors, which could impair macrophage function and initiate the cascade of events in severe infections. We here, add to the hypothesis that immune dysregulation can be caused by the interaction of the SARS-CoV-2 spike glycoprotein via a cryptic epitope with the α7-nAChR in Type-1 macrophages, discuss its implications for the treatment of COVID-19 patients, and present better prospects for the design and dissemination of more effective vaccines and their importance.

How nicotine can inhibit cytokine storm in the lungs and prevent or lessen the severity of COVID-19 infection?

Statistical surveys of COVID-19 patients indicate, against all common logic, that people who smoke are less prone to the infection and/or exhibit less severe respiratory symptoms than non-smokers. This suggests that nicotine may have some preventive or modulatory effect on the inflammatory response in the lungs. Because it is known that the response to, and resolution of the SARS-CoV-2 infection depends mainly on the lung macrophages, we discuss the recent scientific findings, which may explain why and how nicotine may modulate lung macrophage response during COVID-19 infection.