SARS-CoV-2 Interaction with Nicotinic Acetylcholine Receptors

Introduction to SARS-CoV-2 and nAChRs Interaction

The American Thoracic Society suggests that SARS-CoV-2 may interact with nicotinic acetylcholine receptors (nAChRs) as part of its pathophysiology, potentially disrupting the cholinergic anti-inflammatory system and contributing to disease severity, in patients with COVID-19 1, 2
The European Respiratory Society notes that this interaction is theorized rather than proven—viruses primarily enter cells through ACE2 receptors, not nAChRs, but may secondarily affect cholinergic signaling pathways, in the context of SARS-CoV-2 infection 2, 3

The American College of Chest Physicians states that α7 nAChRs normally mediate the cholinergic anti-inflammatory reflex, where acetylcholine acts on immune cells to suppress nuclear factor-κB-dependent transcription, thereby downregulating proinflammatory cytokine production, in healthy individuals 4, 5
The Society of Critical Care Medicine indicates that when this system is disrupted by viral infection, the loss of anti-inflammatory control may contribute to the hyperinflammatory "cytokine storm" seen in severe COVID-19, in critically ill patients 2, 6

The American Heart Association recommends that cigarette smoking increases the risk of poor COVID-19 outcomes, including hospital admission, disease progression, and mortality, despite any theoretical effects of nicotine on receptors, in smokers 1
The American Lung Association notes that smokers have higher baseline inflammation, oxidative stress, decreased phagocytic clearance by macrophages, increased airway permeability, and risk of acute respiratory distress syndrome (ARDS), compared to non-smokers 2, 3
The National Institute of Environmental Health Sciences states that tobacco smoke contains polyaromatic hydrocarbons that cause immune suppression, acrolein that suppresses cytokine production and innate immunity, and carbon monoxide that diminishes oxygen-carrying capacity—all worsening viral infections, in individuals exposed to tobacco smoke 4, 5, 7

The American Academy of Family Physicians advises that nicotine has severe adverse cardiopulmonary effects and is highly addictive, so recreational use of nicotine products should be strongly discouraged, in the general population 2, 3, 8
The World Health Organization notes that nicotine is associated with coronary artery disease, atherosclerosis, aortic aneurysms, peptic ulcers, gastrointestinal cancer, and may promote tumor angiogenesis, in individuals using nicotine products 8
The Centers for Disease Control and Prevention indicates that any potential anti-inflammatory benefits observed in animal models are significantly outweighed by nicotine's harmful effects, particularly its high addiction potential, in the context of nicotine use 8
The European Society of Cardiology states that the effects of nicotine are dose-dependent and context-dependent, with different doses stimulating different (sometimes opposite) effects, in individuals using nicotine products 8

The viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) in the lung or nasopharynx, followed by proteolytic cleavage by transmembrane protease serine 2 (TMPRSS2), as the established mechanism of viral entry, according to the American Thoracic Society 9

Nicotine can stimulate the cholinergic anti-inflammatory response by activating α7 nAChRs, which suppresses nuclear factor-κB-dependent transcriptional events and leads to downregulation of cytokine production, as reported by the European Respiratory Society 9

In animal models, nicotine appears to exert anti-inflammatory effects, decreasing lung vascular permeability and leukocyte infiltration, as observed by the American College of Chest Physicians 10, 11
However, insufficient epidemiological or experimental evidence exists to support the assertion that nicotine might decrease the hyperinflammatory response in people with COVID-19, according to the American Thoracic Society 10, 11

Smoking cessation should be strongly encouraged, as any theoretical anti-inflammatory effects of nicotine are vastly outweighed by the documented harms of tobacco use, as recommended by the European Respiratory Society 12, 13
Combustion products induce oxidative stress, promote inflammation and vascular injury, and establish a prothrombotic state that could promote SARS-CoV-2 infection and contribute to increased severity, as reported by the American Heart Association 9, 12