The Microalgal Diatoxanthin Inflects the Cytokine Storm in SARS-CoV-2 Stimulated ACE2 Overexpressing Lung Cells

Abstract

Contact between SARS-CoV-2 and human lung cells involves the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor on epithelial cells, the latter being strongly involved in the regulation of inflammation as well as blood pressure homeostasis. SARS-CoV-2 infection is characterized by a strong inflammatory response defined as a “cytokine storm”. Among recent therapeutic approaches against SARS-CoV-2 targeting the dramatic inflammatory reaction, some natural products are promising. Diatoms are microalgae able to produce bioactive secondary metabolites, such as the xanthophyll diatoxanthin (Dt). The aim of this study is to demonstrate the anti-inflammatory effects of Dt on the A549-hACE2 lung cell line, exploring its interaction with the ACE2 receptor, as well as depicting its role in inhibiting a cytokine storm induced by the SARS-CoV-2 spike glycoprotein. Results showed that Dt enhanced the cell metabolism, e.g., the percent of metabolically active cells, as well as the ACE2 enzymatic activity. Moreover, Dt strongly affected the response of the SARS-CoV-2 spike glycoprotein-exposed A549-hACE2 cells in decreasing the interleukin-6 production and increasing the interleukin-10 release. Moreover, Dt upregulated genes encoding for the interferon pathway related to antiviral defense and enhanced proteins belonging to the innate immunity response. The potential interest of Dt as a new therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARS-CoV-2 infection is postulated.

The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions

“…We have recently demonstrated that diatoxanthin, a carotenoid derived by marine diatoms, significantly upregulates IL-10 production, increases ACE2 activity, exerts an immunomodulant effect by up-regulating antiviral defense genes and by strongly inhibiting spike-induced inflammatory response in a lung cell line. Diatoxanthin, exclusively found in marine environment, decreases the release of pro-inflammatory mediators responsible for cytokines storm in SARS-COV2 disease, supporting the therapeutic potential of marine-derived bioactive compounds against COVID-19 ( 290 ).…”

In Silico Methodologies to Improve Antioxidants’ Characterization from Marine Organisms

“…Although further studies are needed to elucidate the underlying mechanism, these results provide useful information on the application of these marine carotenoids for the treatment and prevention of COVID-19. Their possible application as a new therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARS-CoV-2 infection has been further supported by the in silico identification and in vitro validation of the binding between xanthophyll diatoxanthin (Dt) and ACE2 protein [ 133 ].…”

<em>Zeaxanthin Epoxidase</em> 3 Knockout Mutants of the Model Diatom <em>Phaeodactylum tricornutum</em> Enable Commercial Production of the Bioactive Carotenoid Diatoxanthin

“…In algae cells, Fx has a main role in light harvesting, and low light (LL) conditions increase the production of this carotenoid [10,14,15]. Recent research has highlighted the pronounced bioactivity of another marine carotenoid, diatoxanthin (Dtx), outperforming commercially available carotenoids as potential disease preventing agents [16][17][18][19]. Antioxidant and anti-inflammatory abilities have been reported where Dtx has lowered the production of reactive oxygen species (ROS) and pro-inflammatory cytokines in vitro [16][17][18].…”

“…Recent research has highlighted the pronounced bioactivity of another marine carotenoid, diatoxanthin (Dtx), outperforming commercially available carotenoids as potential disease preventing agents [16][17][18][19]. Antioxidant and anti-inflammatory abilities have been reported where Dtx has lowered the production of reactive oxygen species (ROS) and pro-inflammatory cytokines in vitro [16][17][18]. Dtx has also been suggested as a potential therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARSCoV-2 infection [18].…”