An algae extract may help prevent the immune overreaction that often causes serious COVID-19 illness


An algae extract may help prevent the immune overreaction that often causes serious COVID illness, Israeli researchers say.

Their study was published in the peer-reviewed journal Marine Biotechnology on experiments in which the extract reduced the severity of artificially induced cytokine storms in a lab.

This is a term used to describe the overproduction of small proteins, called cytokines, which galvanize immune cells to action.

The researchers monitored the production of TNF-α protein – pronounced TNF alpha – one of the key proteins that causes cytokine storms, in different test tubes. Some included just immune system cells and a pathogen that triggers a cytokine storm.

Other test tubes also included an extract from a specially modified version of spirulina, an algae that is attracting scholarly interest for a range of possible but as yet unproven health benefits.

“When the algae extract was included in optimum quantities, there was a 70% reduction in the release of TNF-α proteins, which is very encouraging,” said Dr. Asaf Tzachor, a biotechnology researcher at the Interdisciplinary Center (IDC) in Herzliya, and lead author of the study.

“This indicates that the algae extract may be used to prevent cytokine storms if given to patients soon after diagnosis.”

Clinical trials will start soon, with the aim of producing oral drops, but Tzachor stressed that the research is currently at an early stage. He said that the fact that spirulina is already considered safe in food production and as a dietary supplement — including by America’s Food and Drug Administration — is expected to enable clinical trials to progress quickly.

The algae extract is produced by an Icelandic company, VAXA, which has long championed its qualities when taken as a food supplement in enhancing anti-oxidation, anti-inflammation and anti-tumor activities.

The company has received European Union funding to explore and develop treatments for COVID-19. To do so, it is altering growth conditions of the algae using LED lighting in order to control its metabolic profile, and “enhance” it.

Tzachor’s said that his IDC School of Sustainability and its collaborators, Israeli state-funded Migal Galilee institute and the Icelandic MATIS, have been exploring the algae’s potential on an independent basis and are not receiving funding from VAXA.

The novel coronavirus disease (COVID-19) is an emerging contagious respiratory tract illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al. 2020). From late 2019, SARS-CoV-2 infections have resulted in an array of clinical responses which differ between individual cases, from asymptomatic conditions to detrimental manifestations and mortality.

Whereas precise immune-pathological processes that COVID-19 activates remain, as of yet, contested (Coperchini et al. 2020), there is an ostensible agreement on the major mechanism by which the virus causes severe symptoms.

Epidemiological studies have indicated that exposure to the etiologic agent SARS-CoV-2 provokes macrophages and monocytes to release an excessive amount of different pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, to cause a hypercytokinemia, commonly referred to as a cytokine storm (CS) (Ishikawa 2012; Ye et al. 2020).

An influx of TNF-α, as part of the CS, destabilizes endothelial cell networks and induces damage of vascular barrier, capillary damage, diffuse alveolar damage (DAD), apoptotic cell death, and multi-organ failure. Furthermore, a recent analysis indicated higher systemic levels of IL-2, IL-7, IL-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1A (MIP-1A), and TNF-α, among critically ill COVID-19 patients (McGonagle et al. 2020; Ruan et al. 2020).

Specifically, excess release of TNF-α plays a critical role in disrupting the lung endothelial and epithelial barriers, which may cause acute respiratory distress syndrome (ARDS) (Shimizu 2019). ARDS requires admission to intensive care units (ICU), where invasive mechanical ventilation may be administered (Mittermaier et al. 2020).

Furthermore, it is generally accepted that ARDS is the main cause of death of patients with COVID (Mehta et al. 2020). The prevalence of COVID-19 ARDS incidences led to a global public health emergency, prompting governments to suspend social activities and impose unprecedented movement restriction and social distancing.

These measures were set to maintain ICUs within their operational capacity limitations, a pending public healthcare concern (Alkuzweny et al. 2020; Moghadas et al. 2020).

Considering the role of TNF-α in triggering COVID-19-related cytokine storm syndrome (COVID-CS) and ARDS, it is necessary to develop new approaches for anti-TNF therapy. Indeed, since the outbreak of the pandemic, TNF-α blockers have shown promising outcomes in treating, and mitigating, severe illness (Robinson et al. 2020).

Herein, a novel approach is proposed for TNF-α inhibition, based on a treatment with the blue-green algae Spirulina (Arthrospira platensis) extract.

The potential health benefits of Spirulina are well documented (Belay et al. 1993; Furmaniak et al. 2017). This blue-green algae contains C-phycocyanin (C-PC), a pigment-binding protein, which enhances antioxidation, anti-inflammation, and anti-tumor activities (Cian et al. 2012; Saini and Sanyal 2015).

Furthermore, Spirulina may be cultivated in different conditions and extracted using various techniques, which may affect the bioactive metabolite content of Spirulina (Minhas et al. 2016). Under certain conditions, for instance, irradiation by light-emitting diodes (LED) to control photosynthesis, algal bioactivity such as anti-inflammatory properties may be enhanced (De Morais et al. 2015; Ooms et al. 2016).

In this study, we exposed macrophages and monocytes activated by the pathogenic stimulator lipopolysaccharide (LPS) to different doses of Spirulina extracts, cultivated in either full-range solar spectrum or controlled light conditions. We report that an aqueous extract of a photosynthetically controlled Spirulina (LED Spirulina) inhibits TNF-α secretion by over 70% from LPS-activated macrophages and over 40% from LPS-activated monocyte cells.

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The past three decades have witnessed a tremendous increase in the number of highly pathogenic emerging viruses [1] which have caused serious global threats initiating diverse approaches for understanding the biology of the virus and for robust vaccine and therapeutic development. Coronaviruses are notable examples of zoonotic emerging viruses which can infect a diverse range of mammals and birds including humans [2].

The major outbreak of human coronaviruses occurred in 2003 wherein Severe Acute Respiratory Syndrome (SARS) CoV emerged from Chinese palm civet and caused an epidemic in China with more than 8000 cases including 774 fatal cases [3]. With the help of public health authorities, the outbreak was effectively contained within six months.

Ten years later, another CoV termed Middle East respiratory syndrome (MERS) CoV emerged from dromedary camel to human and is continuing to cause outbreaks in the Middle East region [4]. To date, 2519 cases have been reported with mortality rates of 34% [5].

There is no approved therapy or vaccine available for this virus yet. By the end of 2019, another pandemic coronavirus named Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China [6] though unknown intermediate host. Till now, more than 8,000,000 cases and 450,000 deaths have been reported worldwide [7].

Likewise, novel or re-emerging viral outbreaks may occur in the near future as well. Therefore, effective antiviral and therapeutic strategies are required to control the ongoing or future outbreaks.

Coronavirus spike protein is a promising target for the development of antiviral compounds because their cell tropism is primarily determined by the ability of the spike (S) protein to bind to a host cell surface receptor and can block the virus entry at the early stage of infection. But drug discovery for highly pathogenic viruses like SARS, MERS, Ebola, Lassa, or SARS-2 are challenging due to the requirement for a BSL-3/BSL-4 laboratory containment facility. However, very limited facilities are available, especially in developing countries.

Pseudotyped viruses provide a substitute model in which the native envelope protein of a nonpathogenic BSL-2 virus (vesicular stomatitis virus) replaced with an envelope glycoprotein of a highly pathogenic virus like SARS, MERS, Ebola, or SARS-2 [8]. These viruses mimic a normal virus but are noninfectious in nature.

Moreover, they are replication-incompetent with a single round of infection and hence can be used to do research in the routine BSL-2 laboratories. Pseudotyped viruses have been used in diagnostics, vaccines, and high-throughput screening of entry inhibitors for several BSL-3/BSL-4 level pathogens [8].

Natural products such as plants, algae, and seaweeds have always been implicated in multiple fields of biology for their antibacterial, antiviral, and antifungal properties. Several medicinal plants have been traditionally used to treat viral infections [9] and have been demonstrated with their ability of their inhibitory effects (Table 1) on the replication or entry of several viruses like herpes simplex virus (HSV) type 2, hepatitis B (HBV), influenza virus [10]–[13]and also other emerging viral pathogens such as poxvirus and SARS [14].

Curcumin acts as an antiviral agent against several viruses such as Parainfluenza virus type 3, vesicular stomatitis virus (VSV), HSV, etc. [15]. Diammonium glycyrrhizin the main component of licorice root extract shown to have an inhibitory effect on pseudorabies virus (PrV) [16]. Neem and Tulsi leaf extracts are potent antiviral agents against influenza virus [17], [18]. Moreover, the extract of green tea, another natural compound, inhibits human immunodeficiency virus (HIV), zika virus, influenza virus, and hepatitis C virus (HCV) [19].

Table 1.

Spirulina is a commercially available dietary supplement which has been recorded for its diverse properties. It is a free-floating cyanobacterium, which has 70% protein content and is rich in phenolic acids, essential fatty acids, sulfated polysaccharides, and vitamin B12 [20].

Extracts of Spirulina have been shown to have antiviral activity against multiple enveloped viruses including influenza virus, HSV, adenovirus, etc.[21] Apart from crude plant extracts, several specific compounds from Green tea, catechins, such as epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin-3-gallate (EGCG) have been found to have antiviral and anticarcinogenic properties [22] (Supplementary table 1).

EGCG is a major component and active catechin of green tea and has several bio modulatory effects such as anti-allergic, anti-inflammatory, anti-tumor, antioxidative, and antiviral properties. EGCG, has been reported to inhibit HCV, HIV, HSV type 1 and 2, enterovirus 71, influenza A, and other viruses [10], [23]–[27]. For HIV, EGCG binds to the CD4 molecule at high affinity and inhibits HIV gp120 binding to human CD4+ T cells [28].

Moreover, the EGCG-induced inhibition was observed in a broad spectrum of HIV-1 subtypes as well. EGCG acts through direct inactivation of the virus particle, inhibition of the protease adenain, and intracellular growth in vitro [29]. Sulfated polysaccharides and Spirulan like compounds are the major components of spirulina extract, which inhibits the entry of several viruses including HSV-1, hepatitis A, human cytomegalovirus (HCMV), VSV, and HIV [13].

This clearly shows the importance of antiviral properties of natural compounds, and hence could be promising therapeutic agents for emerging viral diseases including SARS-CoV 2. In this study, we show the biological applications of pseudotyped coronaviruses and the antiviral activity of Spirulina and green tea extracts using the developed pseudotyped coronaviruses.

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