Transient Receptor Potential Vanilloid Subtype 1: Potential Role in Infection, Susceptibility, Symptoms and Treatment of COVID-19

Abstract

The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.

Keywords: COVID-19; SARS-CoV-2; SNPs; TRPV-1; inflammation; pollution; therapy.

Figure 1

(A) TRPV-1 is extensively expressed on neuronal and non neuronal cell membranes, including immune cells and type C sensory nerve fibers of the airways (upper and lower respiratory tract and lung parenchyma). (B) TRPV-1 has been found to be significantly upregulated in numerous viral infections, similarly SARS-CoV-2 is proposed to upregulate the expression of the channel on neuronal and non neuronal cell membranes of infected patients. Adapted from (9).

Figure 2

Simplified depiction of how exposure to air pollutants is proposed to sensitize the sensory to autonomic reflex arc and alter subsequent responses. Inhaled component of air pollution (i.e., DEP), directly sensitizes TRPV-1 (green pathway) located on vagal bronchopulmonary C-fibers endings. Activation of airways sensory nerves (yellow pathway) stimulates neurons in the midbrain (NTS) and, through a neuromodulation process in the CNS, causes the efferent motor responses (red and violet pathways) to the heart (autonomic imbalance) and to respiratory muscles (cough). Adapted from (141).

Figure 3

Interconnection between ACE2, TMPRSS2, and TRPV-1 in SARS-CoV-2 infection. SARS-CoV-2 uses the ACE2 receptor for entry into lung epithelial cells and the host cell serine protease TMPRSS2 for priming the S protein. ACE2 and TMPRSS2 may interact with TRPV-1 through the activation of COX-2 and kininogen pathways. - COX-2 pathway (green pathway). TRPV-1 sensitization is due to the interaction between TRPV-1 and EP receptors (i.e., EP1 and EP3) stimulated by the increase of PGE2 levels in the lungs of affected COVID-19 patients. SARS-CoV-2 interaction with neuroinflammatory cells increases levels of PGE2 a potent inflammatory mediator that is generated by COX-2 conversion of arachidonic acid.- kininogen pathway (red pathway). TRPV-1 sensitization is due to the interaction between TRPV-1 and BK receptors (i.e,. BKB1 and BKB2) stimulated by the increase of BK levels in the lungs. SARS-CoV-2 interaction with neuroinflammatory cells increases levels of BK, referred to as a “Bradykinin Storm.” BK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein. The upregulation of ACE2 in patients with severe symptoms of COVID-19 increases Angiotensin 1–9 levels that in turn raise the levels of BK. High levels of PM in air pollution, such as DEP, directly interact with TRPV-1 (gray arrow) by modulating its activity and increasing its sensitization. This interaction could worsen the outcome of COVID-19 disease in affected patients. Adapted from (42).