Dopamine Reduces SARS-CoV-2 Replication In Vitro through Downregulation of D2 Receptors and Upregulation of Type-I Interferons

Abstract

Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication.

Assessment of the relationship between the dopaminergic pathway and severe acute respiratory syndrome coronavirus 2 infection, with related neuropathological features, and potential therapeutic approaches in COVID‐19 infection

“…175,176 Recently, it was indicated that dopamine can suppress the NLRP3 inflammasome by stimulating its ubiquitination and degradation, which has been related to either D1DR or D2DR pathways. 174 It is critical to explore the interaction between SARS-CoV-2 and dopaminergic receptors and its effects on the respiratory system and immune response. Such information is invaluable for the development of effective COVID -19 treatments.…”

“…It can down-regulate D2 family receptors and may be considered for hindering SARS-CoV-2 infection and restraining hyper-inflammation to prevent tissue damage. 174 Within this view, dopamine or D2 receptor agonists were able to inhibit key pro-inflammatory cytokines, including IL-6 and TNF-alpha, as well as NLRP3/IL-1b and TRL4/ HMGB1 pathways, as an index of COVID-19 severity. 175,176 Recently, it was indicated that dopamine can suppress the NLRP3 inflammasome by stimulating its ubiquitination and degradation, which has been related to either D1-Receptor or D2-Receptor pathways (Figure 7).…”

“…175,176 Recently, it was indicated that dopamine can suppress the NLRP3 inflammasome by stimulating its ubiquitination and degradation, which has been related to either D1-Receptor or D2-Receptor pathways (Figure 7). 174 However, dopamine can damage the immune system during infection.…”

“…In an in vitro study, dopamine produced a strong antiviral effect by the D2 Dopamine receptor agonist (ex., amantadine) and Type‐I IFNs in a dose‐ and time‐dependent manner, probably by elevation of DAT [17 from cells, cells]. Both dopamine and D1 and D2 Dopamine Receptor agonists can inhibit systemic inflammation through the downregulation of inflammatory cytokines and NLRP3 in alveolar and bronchial epithelial cells both in vitro and in vivo, especially in a sub‐chronic protocol 169–171 . D1 receptor antagonists are assumed to be a compensatory cytoprotective response through anti‐replicative effects of dopamine in CaLu‐3 cells, in vitro.…”

Cardiac Arrhythmias in Patients with Myocarditis in the Post-COVID-19 Period

“…Positive chronotropic (e.g. dopamine) agents are considered for atrioventricular block, instead of the transvenous pacemaker to minimize personal protective equipment use and healthcare worker's risk (Limanaqi et al, 2022). It was suggested to postpone permanent pacemaker implantation to allow for an improvement of bradycardia (Kochav et al, 2020).…”