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

Saraiya, Tanmay; Labrou, Dimitrios; Farsalinos, Konstantinos; Poulas, Konstantinos

doi:10.1016/j.fct.2021.112184

Cited by 11 publications

(12 citation statements)

References 32 publications

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“…This nAChR antagonistic action of virus would therefore explain the “cytokine storm” and the hyperinflammatory syndrome observed in several COVID-19 patients [ 9 , 11 ]. Numerous authors also hypothesized a prominent role of macrophages highlighting that the antagonistic action on α7- nAChRs by SARS-CoV-2 determines a dysregulation of the polarization mechanism and a permanence of M1 type macrophages, with a consequent increase in the concentration of inflammatory cytokines [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?

Cafiero

Micera

et al. 2021

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: SARS-CoV-2 pathogenesis has been recently extended to human central nervous system (CNS), in addition to nasopharyngeal truck, eye, lung and gut. The recent literature highlights that some SARS-CoV-2 spike glycoprotein regions homologous to neurotoxin-like peptides might bind to human nicotinic Acetyl-Choline Receptors (nAChRs). Spike-nAChR interaction can probably cause dysregulation of CNS and cholinergic anti-inflammatory pathways and uncontrolled immune-response, both associated to a severe COVID-19 pathophysiology. Herein, we hypothesize that inside the Open Reading Frame (ORF) region of spike glycoprotein, the RNA polymerase can translate small neurotoxic peptides by means of a “jumping mechanism” already demonstrated in other coronaviruses. These small peptides can bind the snAChRs instead of Spike glycoproteins. A striking homology occurred between these small peptides observed by sequence retrieval and proteins alignment. Acting as nAChRs antagonists, these small peptides (conotoxins) could be the explanation for the extrapulmonary clinical manifestations (neurological, hemorrhagic and thrombotic expressions, the prolonged apnea, the cardiocirculatory collapse, the heart arrhythmias, the ventricular tachycardia, the body temperature alteration, the electrolyte K+ imbalance and finally the significant reduction of butyryl cholinesterase (BuChE) plasma levels, as observed in COVID-19 patients. Several factors might induce the expression of these small peptides, including microbiota. The main hypothesis regarding the presence of these small peptides opens a new scenario on the etiology of COVID-19 clinical symptoms observed so far, including the neurological manifestations.

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Section: Introductionmentioning

confidence: 99%

Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?

Cafiero

Micera

et al. 2021

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“…An interaction between the spike protein and AChRs could have pathological consequences not only because it could provide an alternative pathway for the virus to attach to and enter cells, but also because it could disrupt physiological AChR-mediated signaling. Moreover, the notion that the binding of the spike protein to the AChR is competitive with that of small-molecule cholinergic ligands would suggest a novel mechanism by which nicotine consumption and smoking-cessation drugs could affect the course of the disease ( 15 – 17 , 22 – 24 ), the better understood mechanisms being the direct effect of nicotine and its analogs on the α7-AChR–mediated antiinflammatory response to viral infection ( 25 – 29 ).…”

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confidence: 99%

An experimental test of the nicotinic hypothesis of COVID-19

Godellas

Cymes

Grosman

2022

Proc. Natl. Acad. Sci. U.S.A.

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The pathophysiological mechanisms underlying the constellation of symptoms that characterize COVID-19 are only incompletely understood. In an effort to fill these gaps, a “nicotinic hypothesis,” which posits that nicotinic acetylcholine receptors (AChRs) act as additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptors, has recently been put forth. A key feature of the proposal (with potential clinical ramifications) is the suggested competition between the virus’ spike protein and small-molecule cholinergic ligands for the receptor’s orthosteric binding sites. This notion is reminiscent of the well-established role of the muscle AChR during rabies virus infection. To address this hypothesis directly, we performed equilibrium-type ligand-binding competition assays using the homomeric human α7-AChR (expressed on intact cells) as the receptor, and radio-labeled α-bungarotoxin (α-BgTx) as the orthosteric-site competing ligand. We tested different SARS-CoV-2 spike protein peptides, the S1 domain, and the entire S1–S2 ectodomain, and found that none of them appreciably outcompete [ 125 I]-α-BgTx in a specific manner. Furthermore, patch-clamp recordings showed no clear effect of the S1 domain on α7-AChR–mediated currents. We conclude that the binding of the SARS-CoV-2 spike protein to the human α7-AChR’s orthosteric sites—and thus, its competition with ACh, choline, or nicotine—is unlikely to be a relevant aspect of this complex disease.

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“…The so‐called cholinergic anti‐inflammatory reflex is a construct that is standing on the α7nAChR. Some studies predict a direct interaction between SARS‐CoV‐2 spike glycoprotein with α7nAChR, which could impair the effectiveness of CAP and initiate the cascade of events in COVID‐19 55 …”

Section: Sars‐cov‐2 Interaction With α7nachrmentioning

confidence: 99%

“…Tanmay et al . highlighted the idea that COVID‐19 has similar characteristics to other inflammatory conditions that have imbalanced type 1 macrophages/type 2 macrophages ratios, and activation of α7nAChR in those diseases has shown alleviating impact 55 . In COVID‐19, immune dysregulation can be caused by the interaction of the underlying virus with the α7nAChR in type 1 macrophages that express α7nAChR 56,57 .…”

Section: Sars‐cov‐2 Interaction With α7nachrmentioning

confidence: 99%

Inflammatory reflex disruption in COVID‐19

Hajiasgharzadeh

Jafarlou

Mansoori

et al. 2022

Clinical & Exp Neuroim

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was identified in Wuhan, China, in late 2019 and caused coronavirus disease 2019 (COVID‐19), which is still a global pandemic. In most infected people, SARS‐CoV‐2 can only cause moderate symptoms, while in other patients, it leads to severe illness and eventually death. Although the main clinical manifestation of COVID‐19 is often seen in the lungs, this disease affects almost all body organs. The excessive and prolonged release of inflammatory cytokines that may occur in COVID‐19 patients, known as cytokine storms, stimulates undesired immune responses and can cause various tissues damage. In the current review article, we focus on the potential advantages of the intrinsic cholinergic anti‐inflammatory pathway (CAP) as the efferent arm of inflammatory reflex in COVID‐19 management. Considering this endogenous protective mechanism against chronic inflammation, we focused on the effects of SARS‐CoV‐2 in the destruction of this anti‐inflammatory system. Several studies indicated the interaction of SARS‐CoV‐2 with the alpha7 subtype of the nicotinic acetylcholine receptor as the effector molecule of the inflammatory reflex. On the other hand, neurological manifestations have increasingly been identified as significant extrapulmonary manifestations of COVID‐19. The rational connection between these findings and COVID‐19 pathogenesis may be an important issue in both our understanding and dealing with this disease. COVID‐19 is deeply rooted in our daily life and requires an urgent need for the establishment of effective therapeutic options, and all the possible treatments must be considered for the control of such inflammatory conditions.

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

Cited by 11 publications

References 32 publications

Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?

Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?

An experimental test of the nicotinic hypothesis of COVID-19

Inflammatory reflex disruption in COVID‐19

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