key: cord-0979342-tg3od3iw authors: Farsalinos, Konstantinos; Niaura, Raymond; Le Houezec, Jacques; Barbouni, Anastasia; Tsatsakis, Aristidis; Kouretas, Dimitrios; Vantarakis, Apostolos; Poulas, Konstantinos title: Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system date: 2020-04-30 journal: Toxicol Rep DOI: 10.1016/j.toxrep.2020.04.012 sha: 7b83312ee63e850dbd9681954aa865e9d26894a1 doc_id: 979342 cord_uid: tg3od3iw nan As of 20 April, almost 1.7 million people globally have been diagnosed with Corona Virus Disease 2019 , a pandemic that has evolved from the emergence of a new coronavirus strain, acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in China. More than 170,000 deaths have been reported, while there are certainly many more cases of milder disease that have not been diagnosed and officially confirmed due to limited testing capacity in most countries. The pandemic is a global emergency due to the rapid transmission of the disease and the potential to overwhelm the healthcare systems, and is expected to have considerable economic and health impacts. Possible contributing factors, their possible role in the relatively high infection, death rates between countries and origin have recently been studied (Goumenou et al. 2020a , Goumenou et al. 2020b ). This new outbreak has been additionally evaluated for current knowledge on coronaviruses based on a short history to epidemiology, pathogenesis, clinical manifestation of the disease, as well as treatment and prevention strategies (Docea et al 2020) . The search for potential protective and therapeutic antiviral strategies is of particular and urgent concern (Skalny et al., 2020) . While in most cases, especially in young people without any comorbidities, the disease is expected to be relatively mild, there is a substantial proportion of patients who develop complications and need intensive care-unit support and mechanical intubation. In one case series of 1099 patients in China (Guan et al., 2020) , 6.1% of cases suffered from the primary composite end-point of admission to an intensive care unit, the use of mechanical ventilation, or death. Patients with severe disease typically present with dyspnea and hypoxemia shortly after disease initiation, and may quickly progress to respiratory failure, acute respiratory distress syndrome (ARDS) and multi-organ failure (Chen et al., 2020) . Predictors of adverse outcomes include J o u r n a l P r e -p r o o f elevated levels of inflammatory markers and pro-inflammatory cytokines. A study of 150 COVID-19 cases reported that elevated levels of C-reactive protein (CRP), ferritin and IL-6 were associated with death (Ruan et al., 2020) . IL-6, an important pro-inflammatory cytokine, was elevated in fatal cases of COVID-19 in another study of 191 patients (Zhou et al., 2020) . Another study of 452 patients reported that those with severe disease showed lymphocytopenia, neutrophilia, low levels of monocytes, eosinophils and basophils, and elevated levels of infection-related biomarkers and inflammatory cytokines (Qin et al., 2020) . Pathological examination of a case in China revealed bilateral diffuse alveolar damage, desquamation of pneumocytes, hyaline membrane formation and interstitial mononuclear inflammatory infiltrates (Xu et al., 2020) . Flow cytometry of peripheral blood revealed reduced levels of CD4+ and CD8+ T cells, which however were hyper-activated, and elevated concentration of proinflammatory CCR6+ Th17 in CD4+ T cells. Such findings are hallmarks of ARDS and resemble features observed in SARS and Middle Eastern Respiratory Syndrome (Ng et al., 2016; Ding et al., 2003) . Systemic vasculitis was also observed (Xu et al., 2020) . Therefore, it seems that immune dysregulation may be implicated in the pathophysiology of severe COVID-19. While for decades common thinking suggested that every immune response to antigenic invasion was always beneficial in averting potential damage, studies in the 1980s identified that immune cells produce proteins with pleiotropic properties, having the potential to be either beneficial or harmful (Tracey, 2007) . The proteins, called cytokines, were found to cause clinical manifestations similar to sepsis such as hemodynamic instability, fever, and localized inflammation (Tracey et al., 1986; Dinarello et al., 1986) . Cytokines are important in mediating both immune cell recruitment and complex intracellular signaling control mechanisms that They are expressed by numerous cells, including macrophages, monocytes, B cells and T cells, promote differentiation of T-helper cells and stimulate CD4+ cells (Turner et al., 2014) . While activation of the immune system is important in fighting pathogens, dysregulation of cytokine production may lead to uncontrolled effects that can ultimately be detrimental to health (Dinarello, 2007; Turner et al., 2014) . Several animal experimental models inducing pro-inflammatory cytokines, such as sepsis, ischemia-reperfusion and pancreatitis have shown that vagus stimulation improves outcomes. This effect is mediated by the nicotinic acetylcholine receptor (nAChR) α7 subunit on macrophages (Wang et al., 2003) . Mice deficient of the α7 subunit exhibited increased endotoxin-induced TNF production, and electrical vagus innervation failed to reduce serum TNF levels (Wang et al., 2003) . B-lymphocytes also express α7 nAChRs. Macrophages appear to be very sensitive to acetylcholine, which suggests that any source of acetylcholine, even from nonneuronal sources such as epithelial and endothelial cells, could also modulate the activity of adjacent macrophages (Tracey, 2002) . Besides TNF, other pro-inflammatory cytokines are inhibited by acetylcholine, such as high mobility group B1 (HMGB1), IL-1, and IL-6 (Ulloa, 2005 ). Modulation of inflammatory and immune response by the central nervous system (CNS) through the vagus nerve is based on bi-directional communication between the immune and nervous systems. Afferent vagus nerve fibers, located in nucleus tractus solitarius, provide sensory input to the CNS about the inflammatory status that can result in the transmission of efferent signals, originating from the dorsal motor nucleus, to control the inflammatory response (Pavlov et al., 2003) . Such a response is rapid and localized, unlike the diffusible anti-inflammatory network, which is slow, distributed, non-integrated and dependent on concentration gradients (Tracey, 2002) . Smoking is known to increase the risk for respiratory infection susceptibility and severity (Cohen et al., 1993; Millett et al., 2015) . Considering that COVID-19 was declared by the World Health Organization as a pandemic, a substantial disease burden would be expected among the estimated 1.1 billion smokers, especially in countries with high smoking prevalence. Therefore, there were understandable concerns about this population subgroup (Berlin et al., 2020) . Additionally, smoking-related disease conditions such as cardiovascular disease and COPD are also established risk factors for adverse outcomes in COVID-19 (Wu & McGoogan, 2020) . China was the first country to be affected by the pandemic and has a high smoking prevalence. In 2018, the population smoking prevalence was 26.6% with a much higher prevalence in men (50.5%) than in women (2.1%) (World Health Organization, 2018). Therefore, a high smoking prevalence among patients with COVID-19 would be expected, even if smoking did not adversely affect disease susceptibility and severity. It is obviously inappropriate to suggest that anyone should initiate smoking or to continue to smoke due to the well-established smoking-related morbidities and the large number of potentially toxic chemicals in cigarette smoke. Furthermore, it is unlikely that any other compound in tobacco cigarette smoke, besides nicotine, would be implicated to the potential benefits observed in smokers. Moreover, due to the adverse effects of smoking and the fact that many smokers would suffer from co-morbidities (such as cardiovascular disease, COPD etc.), it is expected that the potential benefits of nicotine would be blunted when observed in smokers. Nicotine is a cholinergic agonist. Therefore, it is an important inhibitor of pro-inflammatory cytokines acting through the cholinergic anti-inflammatory pathway via α7-nAChRs. Nicotine A prominent feature of COVID-19 is coagulopathy that results in thromboembolic complications. Venous thromboembolism was reported in 25% of patients who were not under thromboprophylaxis, and was associated with higher mortality rate (Cui et al., 2020) . Abnormal coagulation parameters were also associated with poor survival (Tang et al., 2020) . Although antagonists of acetylcholine on α7-nACh receptor with high affinity, we decided to explore the hypothesis that SARS-CoV-2 may have acquired sequences by any of the potential, and not defined yet, intermediates through genomic recombination. We compared the protein sequences between SARS-CoV-2 and snake venom neurotoxins. We were able to identify regions with four or five amino acids homology between the coronavirus and several neurotoxin molecules (e.g. SARS-CoV-2 compared with alpha Bungarotoxin, Fig 1A; SARS-CoV-2 and alpha-Cobratoxin, Fig 1B) . J o u r n a l P r e -p r o o f Therefore, we hypothesize that these sequences on the SARS-CoV-2 proteins, being similar to the active sites of a neurotoxin, can result in binding to nAChRs and adversely affecting their function by preventing the action of acetylcholine. Nicotine could act as a competitive agonist for the nAChRs that could restore the compromised function of the nicotinic cholinergic system. This may be feasible through repurposing already approved (for other indications) pharmaceutical nicotine products such as nicotine patches for use by non-smokers, or even by using these products as already indicated (i.e. as smoking substitutes) among current smokers. These products are available over-the-counter in most countries. They have been administered therapeutically in non-smokers for neurological conditions and inflammatory bowel disease for larger periods than would be needed for COVID- Clinical trials will dictate future approaches and the role of nicotine in COVID-19, while further experimental studies should examine the affinity of the virus to nAChRs. In conclusion, we noticed that most of the clinical characteristics of severe COVID-19 could be explained by dysregulation of the cholinergic anti-inflammatory system. The observation that patients eventually develop cytokine storm which results in rapid clinical deterioration, led to the development of a hypothesis about the series of events associated with adverse outcomes in COVID-19 (Fig. 2) . Once someone is infected with SARS-CoV-2, the immune system is mobilized. As the virus replicates, cell and viral debris or virions may interact with the nAChRs blocking the action of the cholinergic anti-inflammatory pathway. If the initial immune response is not enough to combat the viral invasion at an early stage, the extensive and prolonged replication of the virus J o u r n a l P r e -p r o o f will eventually block a large part the cholinergic anti-inflammatory pathway seriously compromising its ability to control and regulate the immune response. The uncontrolled action of pro-inflammatory cytokines will result in the development of cytokine storm, with acute lung injury leading to ARDS, coagulation disturbances and multiorgan failure. Based on this hypothesis, COVID-19 appears to eventually become a disease of the nicotinic cholinergic system. Nicotine could maintain or restore the function of the cholinergic anti-inflammatory system and thus control the release and activity of pro-inflammatory cytokines. This could prevent or suppress the cytokine storm. This hypothesis needs to be examined in the laboratory and the clinical setting. Ethics approval and consent to participate. Not applicable. Clinical Characteristics of Coronavirus Disease 2019 in China Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms Cytopathology or immunopathology? 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The authors report no competing interests for the past 36 months. No funding was provided for this study.