Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This respiratory illness was declared a pandemic by the world health organization (WHO) in March 2020, just a few weeks after being described for the first time. Since then, global research effort has considerably increased humanity's knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19. However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population and the threat of a complete immune escape variant, alternative strategies in the fight against SARS-CoV-2 are urgently required. Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies. In this review, we introduce the pivotal role of calcium signaling in viral infection cascades. Based on this, we discuss prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.

Keywords: Ca2+ channels; SARS-CoV-2; calcium; therapeutics; viral infections.

Figure 1

Strategies for inhibition of cellular calcium transport systems involved in viral infection cascades. Calcium levels dictate the activity of the NLRP3 inflammasome, eventually leading to pyroptosis of the cell. CCBs have been shown to interact with TRP, L-type Ca²⁺ channels as well as ACE2 and thus have the potential to inhibit SARS-CoV-2 endocytosis. Auxora is a specific inhibitor of the STIM/Orai system, which has been implicated in inflammation-induced injury of pulmonary endothelial cells as well as proinflammatory cytokine storms that contribute to severe COVID-19 disease. There is evidence that TRPML2 channels have a role in the endocytosis of SARS-CoV-2 into host cells. Potential drugs designed for these channels could be strong tools in the treatment of COVID-19. CBD decreases expression of ACE2 and TMPRSS2, which are both integral players in SARS-CoV-2 infection. Double-membrane vesicles (DMVs) are derived from ER membranes and formed by non-structural proteins (NSPs) 3–6 to facilitate viral RNA replication in separate compartments, as it would be impaired by immune-responses in the cytosol. HSP27 vaccination might attenuate inflammation and increase tissue regeneration. Inhibition of ERp57 might impair correct spike-folding during virus replication. Knockout/knockdown of the Sigma-1 receptor has been shown to reduce viral replication, Numbers in bubbles denote sections describing the indicated proteins and mechanisms in detail.