The battle against COVID-19 has taken significant strides in combatting acute infections, but the emergence of Long COVID or Post-Acute Sequelae of COVID-19 (PASC) presents a new challenge. PASC is a complex syndrome that affects multiple organs and includes symptoms such as cognitive impairment, fatigue, disordered sleep, and memory loss. Researchers are now studying the role of cholinergic mechanisms, specifically α7 nicotinic acetylcholine receptors (α7 nAChRs), to better understand both acute COVID-19 and its long-term effects.
Studies have shown that the SARS-CoV-2 virus, responsible for COVID-19, can bind to nicotine acetylcholine receptors, with a particular focus on α7 nAChRs. These receptors are found in various cells in the body and have a role in neurotransmitter and cytokine release, as well as modulating the release of pro-inflammatory cytokines. This anti-inflammatory function is of interest in the context of the hyperinflammation seen in COVID-19.
Research has revealed that SARS-CoV-2 directly interacts with α7 nAChRs, specifically through the SARS(674-685) peptide. This interaction has a dual effect on the receptors, activating and diminishing their channel activity. Other fragments of the virus, like the 381-386 fragment, bear similarity to snake venom toxins, further complicating the virus’s interaction with nicotinic receptors.
Animal studies have shed light on the effects of the SARS(674-685) peptide on α7 nAChRs. Mice immunized with this peptide exhibited an inflammatory response and cognitive impairment, resembling Long COVID symptoms. However, interventions with α7 nAChR agonists and allosteric modulators alleviated these effects, suggesting potential therapeutic approaches.
The presence of specific antibodies targeting the SARS(674-685) peptide and α7(179-190) in individuals who have had COVID-19 underscores the intricate relationship between the virus, the immune system, and α7 nAChRs. These antibodies may contribute to the cognitive impairments observed in Long COVID patients.
Building upon these findings, therapeutic strategies for both acute COVID-19 and Long COVID can be explored. Stimulating α7 nAChRs with agonists and modulators may help reduce viral penetration and inflammation during acute infection. Furthermore, α7-selective agonists and protein-conjugated α7(179-190) could disrupt the detrimental antibody loop seen in Long COVID. Repurposed drugs like hydroxyurea, which modulates α7 nAChRs, might also hold promise for Long COVID treatment.
In conclusion, the role of α7 nicotinic acetylcholine receptors in COVID-19, encompassing both acute infection and Long COVID, is an area of active investigation. Understanding the intricate interactions between the virus and these receptors may open doors to new therapeutic interventions. As research progresses, targeting α7 nAChRs offers hope in unraveling the mysteries of Long COVID and providing relief to those affected by its persistent consequences.