As reported in previous studies (Feldmann et al. 2020), critically ill COVID-19 patients who were administered a single dose of a TNF-\(\alpha\) neutralizing antibody were 45% less likely to die overall, and more likely to be weaning from mechanical ventilation 1 month after treatment, compared with untreated patients. This suggests that control of CS in its early stage through such means as immunomodulators and cytokine antagonists, as well as reduction of lung inflammatory cell infiltration, is key to reducing COVID-19-related mortality rates.
This study showed that LED Spirulina extract in low doses is able to decrease excessive release of TNF-α in LPS-activated macrophages and LPS-activated monocyte cells by over 70% and 40%, respectively. If further clinical trials confirm these efficacy rates among human subjects, then LED Spirulina may act as a novel TNF-α suppressor.
The substantial inhibitory effect of LED Spirulina on TNF-α secretion, in contrast to an unsubstantial effect on IL-6 release, prompts us to assume that the LED Spirulina extract serves as a specific TNF-α suppressor.
It should be emphasized that LED Spirulina’s anti-TNF-α effect exhibited a reversed dose-response activity. This might suggest that very low doses of LED Spirulina extract-related active molecules can affect endpoints (Vandenberg 2014). A similar effect was shown in other plant-based whole extracts, exhibiting the highest activity at the lowest concentration (Otegbade et al. 2017).
A possible explanation for the reaction pattern observed in this study for TNF-α and IL-6 inhibition is that different bioactive molecules of LED Spirulina extract at different absolute quantities affect macrophages and monocyte cells differently, with some bioactive molecules suppressing TNF-α at low dosages, while others inhibit IL-6 release only at higher dosages.
In addition, since both Solar and LED Spirulina extracts include CPC, the cytokine inhibitory bioactivity of the LED Spirulina extract could not be explained by the presence of this molecule alone (Jiang et al. 2017). Furthermore, according to previous studies (Cherng et al. 2007), using pure CPC on LPS-activated macrophages results in 40% TNF-α inhibition at 250 μg/mL. Here, we show inhibitory effect of 70% at 0.1 μg/mL of LED extract, suggesting that CPC is not the only responsible compound for TNF-α inhibition. As there are indications that sorbitol and adenosine derivate have anti-inflammatory properties (Mongkhon et al. 2014), the upregulation of these groups in LED Spirulina compared with Solar Spirulina leads us to suggest that the bioactivity of LED Spirulina extract results from a synergistic effect between several functional groups that might include CPC, sorbitol, and adenosine derivate.
Lastly, in order to preserve a multi-batch consistent bioactivity of the extract, it is essential that the algal biomass is cultivated under consistent and controlled conditions throughout the year (e.g., light composition, irradiation level, temperature, pH levels). Such cultivation conditions may be realized in a fully controlled, indoor system, uninterrupted by diurnal or seasonal variations.
Implications and Future Research
We suggest at least three advantages of this novel approach of a natural, algae-based CS shield, and note that it requires further research.
First, as TNF-α is a key player in many acute inflammatory reactions, acting as an amplifier of inflammation, algae-based anti-TNF blockade has the potential to assist in treating other virus-induced CS, such as COVID-19, influenza, and autoimmune-related inflammatory diseases.
Second, and on condition that in vivo experiments establish the effectiveness of LED Spirulina in reducing CS, our proposed novel treatment could be dispensed extensively without putting the health of patients at risk, since Spirulina is FDA approved as a dietary supplement, and since its administration is non-intrusive, and can be orally absorbed.
Third, if animal and clinical trials confirm the efficacy of this anti-TNF therapy at the rates reported above, and the substance is available to the general population, a robust therapeutic intervention can be expected that is independent of vaccines, their requisites and potential ramifications, including skilled healthcare workers in clinics and possible side effects, especially in vulnerable populations with chronic diseases, which could only be detected in phase IV clinical trial years after administration.
Concomitantly, an algae-based anti-TNF therapy should be unaffected by variations in SARS-CoV-2 genome across major mutation clusters (Toyoshima et al. 2020), including recent mutations in SARS-CoV-2 that have raised concerns in regard to vaccine efficacy (Korber et al. 2020; Kupferschmidt 2020).
An ancillary, yet substantial benefit, such as therapeutic intervention—should it be proven efficient in human subjects—will free up capacity of ICUs, enable patients to receive over-the-counter affordable treatment option.
Drawing on our in vitro results, we stress the need for prompt in vivo studies to assess the effectiveness of various Spirulina extracts among animal models, as well as in clinical trials.
In addition, future research should note that the effect on TNF-α expression was greater than on IL-6. This finding suggests that the extract targets TNF-α secretion selectively and further validation with a more detailed mechanism of the anti-inflammation cascade within macrophages and monocyte cells should be explored.
It should likewise be noted that the extract from the LED-controlled cultivation process was significantly more effective at suppressing release of TNF-α. To date, no natural compound has been proven to suppress specifically TNF-α. Therefore, LED Spirulina could pave the way for novel algae-based bioactive compounds as anti-TNF treatment.