Content

The spike protein (S) of SARS-CoV-2 binds to the ACE2 receptor, which is expressed by alveolar cells of the lungs, epithelial cells of the nose and intestines, and vascular endothelial cells. After binding to ACE2, S proteins are cleaved by the cellular enzyme TMPRSS2. As a result, the cell membranes and SARS-CoV-2 fuse, the SARS-CoV-2 gene is released into the cell, and the virus begins to multiply.

Certain nutrients stimulate the innate and acquired immune systems and contribute to antiviral resistance. The combined effect of multiple nutrients can be broader than that of individual drugs, and therefore effectively prevent infection or suppress SARS-CoV-2.

Brazilian scientists have investigated how the combination of substances and drugs such as increases the immune coronavirus response:

Zinc, vitamin D3, glutamine, and OncoTherad share a common mechanism of action: These drugs improve the response of interferons and antiviral signaling molecules.

Nutrient deficiencies can interfere with the treatment of COVID-19, while the synergistic effects of zinc, vitamin D3, glutamine, and OncoTherad can provide preventive and curative effects against COVID-19.

Antiviral Response of Interferon To SARS-Cov-2

Once the virus has infected cells, intracellular pattern recognition receptors detect the presence of foreign molecules. In addition, TLR pattern recognition receptors detect viral nucleic acids. These TLRs include TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9.

The interaction of foreign molecules with pattern recognition receptors triggers an antiviral immune response – cells produce interferon and other inflammatory signaling molecules (cytokines) that have an antiviral effect and inhibit the multiplication of infected cells.

Interferons (IFNs) are the first line of defense against viral infections. In response to the penetration of the virus, infected and immune cells secrete IFN. IFN binds to receptors on the cell surface and triggers the expression of interferon-stimulated genes (ISG), which suppress viral replication both in the infected cell and in neighboring cells.

A fast and effective immune response is essential to limit the spread of the virus. However, excessively high serum levels of pro-inflammatory cytokines and chemokines cause uncontrolled systemic inflammation that increases the severity of viral infections such as influenza, SARS-CoV-2, and other coronaviruses. Interferons can suppress inflammation. They decrease the production of such pro-inflammatory cytokines like IL-1, IL-18, and IL-12 and increase the production of the anti-inflammatory cytokine IL-10.

Uncontrolled systemic inflammation is the primary mechanism of acute respiratory distress syndrome (ARDS), the leading cause of death from COVID-19. Therefore, interferons play an important role in treating COVID-19, not only through their antiviral effects but also through balancing the cytokine storm.

SARS-CoV-2 suppresses the production of interferons. Suppression of IFN is associated with severe COVID-19 and increased mortality:

  • Decreased IFN-γ expression in helper T cells is associated with severe COVID-19.
  • A Chinese study on human lung tissue samples showed that SARS-CoV-2 does not result in IFN I, II, or III expressions.

Interferons are used to treat and prevent COVID-19.

OncoTherad

OncoTherad helps the immune system eliminate cancer and may improve the effectiveness of SARS-CoV-2 prevention and treatment. Phase I / II preclinical, veterinary, and clinical trials have shown that OncoTherad stimulates innate immunity by activating the interferon system.

OncoTherad activates the TLR2 and TLR4 receptors, which leads to an increase in IFN production. In addition, it promotes the activation of killer T cells, dendritic cells, and pro-inflammatory macrophages. Since SARS-CoV-2 suppresses the interferon system and OncoTherad promotes IFN production, this drug may help fight SARS-CoV-2 infection and reduce the severity of lung damage.

Clinical researches

  • Clinical use of OncoTherad for COVID-19 showed that in 5 patients who developed severe COVID-19 during treatment for non-muscle-invasive bladder cancer, OncoTherad administration with corticosteroids and antibiotics mitigated exacerbation of the inflammatory response in the lungs, reduced the average length of stay in the hospital from 18 to 10 days and prevented the need for intubation.
  • Another study describes a clinical case of a 78-year-old Brazilian man with BCG-resistant recurrent muscular-non-invasive bladder cancer. The patient had PCR-confirmed COVID-19 and an acute inflammatory process in the lungs. Before infection with SARS-CoV-2, the patient was prescribed OncoTherad for cancer treatment: one intravesical and one intramuscular injection per week for 4 weeks. The patient interrupted therapy for 2 weeks to go on a trip. After showing symptoms of COVID-19 and admission to the hospital, the patient continued to take OncoTherad with a single intramuscular injection for cancer treatment. The COVID-19 treatment regimen included oxygen therapy (nasal catheter flow 4 L / min), ceftriaxone 2 g (for 6 days, IV), azithromycin 500 mg (for 6 days, IV) and Tamiflu 75 mg (2 times daily within 5 days, orally). 72 hours after hospitalization, the symptoms of a runny nose and cough improved, and the fever disappeared. However, the patient persisted in loss of appetite and fatigue with minimal exertion. Oxygen therapy was continued, and after 6 days of hospitalization, the patient showed a significant improvement in pulmonary inflammation (saturation 94% at room temperature). Oxygen therapy was canceled, a significant clinical improvement was observed on the 8th day of illness (saturation 98%, decreased signs of pneumonia, no fever, decreased cough, and increased appetite). The patient was discharged on the 10th day of hospitalization in good general condition.

A Chinese study found that 86% of patients with SARS-CoV-2 infection were discharged after 16 days of hospitalization, with radiological deterioration on day 7 and improvement on day 14. In addition, a Brazilian patient treated with OncoTherad recovered in a shorter time (10 days) than usual with COVID-19.

Considering the comorbidities and the age of the patients, scientists believe that OncoTherad was protective, preventing the infection from progressing to severe COVID-19 and promoting a quick recovery without the need for hospitalization in an intensive care unit.

Zinc

Previous research has shown that zinc has antiviral effects against SARS-CoV, rhinovirus, influenza, herpes virus, respiratory syncytial virus, hepatitis E, and transmissible gastroenteritis virus. Dutch scientists have shown that zinc inhibits viral replication in cells infected with SARS-CoV. In viral infections, zinc enhances interferon signaling. In turn, interferons stimulate the influx of zinc into infected cells. That highlights the importance of zinc for interferon signaling.

Zinc stimulates the production of IFN-α and IFN-γ and enhances the antiviral effect of IFN-α. American scientists have shown that zinc and the ZIP8 zinc cell transporter regulate the expression of IFN-γ in activated human T-lymphocytes. Zinc at a dosage of 15 mg/day orally increased IFN-γ production by activated T lymphocytes.

Zinc is a vital factor in protecting the lung epithelium from acute damage. American scientists have shown that the absence of zinc, IFN-γ, TNF-α, and activation of the death receptor Fas on the cell surface can lead to the death of lung epithelial cells and dysfunction of the pulmonary epithelial barrier.

A German study found that zinc deficiency is associated with increased susceptibility to infections. The reason is the deterioration in the transmission of interferon signals. In contrast, elevated zinc concentrations can restrict hepatitis E virus replication by increasing the efficiency of IFN signalling and the production of antiviral ISGs in response to the interferon signal.

Interferon triggers the synthesis of membrane proteins IFITM in the cell. These proteins have antiviral properties. Scientists at Harvard Medical School in the United States have shown that IFITM proteins play a crucial role in suppressing enveloped viruses such as influenza A and Ebola. Zinc metalloproteinase (protein ZMPSTE24) exhibits the same antiviral activity. Zinc stimulates the interferon response to enveloped virus infection, and interferon triggers the synthesis of the antiviral proteins IFITM3 and ZMPSTE24. Since SARS-CoV-2 is an enveloped virus, scientists suggest that zinc-induced increases in IFITM and/or ZMPSTE24 proteins may effectively combat COVID-19.

Zinc is essential for signaling receptors in immune cells. One of the receptors is TLR4, which recognizes viral nucleic acids and is involved in the immune response to infection. Upon activation, TLR4 causes an increase in free zinc ions, which are required for the expression of inflammatory cytokines that contribute to antiviral protection.

Zinc Deficiency Causes Taste and Saliva Disturbances in COVID-19

COVID-19 can cause gustatory and salivation. Sometimes these symptoms persist for up to one year after recovering from COVID-19.

Japanese scientists have found that gustatory and salivation are associated with zinc deficiency.

Zinc is essential for taste perception and saliva secretion. It is present in high concentrations in taste buds and salivary gland cells. Zinc deficiency leads to a decrease in taste sensitivity and impaired salivation.

Zinc deficiency is part of the immune coronavirus response. Coronavirus leads to zinc deficiency. Serum zinc levels in patients with COVID-19 are significantly lower than those without COVID-19 and healthy controls. A decrease in serum zinc concentration is one of the immune response mechanisms. This mechanism suppresses viral replication, impairing the availability of zinc to the virus, and activates immune cells to destroy the infection.

COVID-19 causes taste disturbances by infecting the cells of the taste buds and salivary glands. By penetrating the taste buds and cells of the salivary ducts and glands, SARS-CoV-2 damages them and therefore can cause disturbances in taste and saliva secretion. Viral infection and inflammation of the salivary glands leading to a change in the composition of saliva. Moreover, the shift in taste is associated with a difference in the rate of salivation and the concentration of salivary components, including zinc and zinc-binding protein.

Zinc supplements may speed up taste recovery after COVID-19. Because zinc deficiency is associated with taste and salivation disorders, zinc supplements may reduce oral symptoms in patients with COVID-19. However, zinc overdose can lead to oxidative stress and tissue damage. Therefore, zinc supplements should only be taken with a doctor’s prescription.

Details of the study are described in the article “Zinc Deficiency Affects Taste Changing After COVID-19.” The study was published in MDPI’s Life magazine.

Zinc Enhances Interferon Synthesis in The Elderly, But an Overdose of Zinc Disrupts the Immune System

With age, immune cells produce less IFN-α in response to a viral infection, confirmed by a study by German scientists involving 468 people aged 1 to 90 years. In addition, older people absorb zinc worse than younger people. At the same time, zinc deficiency impairs immune responses and wound healing.

Scientists at the University of Lübeck (Germany) investigated how zinc supplements affect interferon-alpha production by immune cells in people of different ages. The average age of the older participants was 73, while the young participants were 28.

The total number of immune cells in the elderly and young differed slightly. However, IFN-α synthesis was significantly higher in younger participants (white bars) than in older ones (black bars):

Image source: https://www.liebertpub.com/doi/10.1089/jir.1997.17.469

A zinc solution at a concentration of 15 μM increased the production of IFN-α in both groups of participants. In the elderly, the synthesis of interferon-alpha increased to the level of the young. The optimal zinc concentration to stimulate the production of IFN-α was 15-25 µM.

Excessive intake of zinc impairs the functioning of the immune system. Concentrations above 50 μM suppressed the interferon-alpha synthesis: the interferon level was lower than without adding zinc solution.

Details of the study can be found in the article Zinc Supplementation Enhances Interferon Synthesis in the Elderly. The study was published in the Journal of Interferon & Cytokine Research.

Clinical researches

  • An Italian study of 21 healthy older adults (mean age 87) found that consuming zinc-fortified milk (3 mg added zinc plus 1 mg zinc naturally present in milk) for 2 months increased cellular immunity. It is evidenced by an increase in the levels of IFN-γ and IL-12p70 in peripheral blood samples in response to stimulation with endotoxin and an increase in endocrine activity in the thymus.
  • Another study in 19 healthy older adults who received 10 mg elemental zinc (50 mg zinc aspartate) also showed that zinc supplementation significantly increased the release of the pro-inflammatory cytokines IFN-γ and TNF-α. It confirms that zinc supplementation improves the immune response of T lymphocytes.

Vitamin D

Vitamin D3 is a hormone produced in the body and regulates >200 genes in various cell types. Vitamin D3 is converted to its active form (calcitriol) by the enzyme 1α-hydroxylase (CYP27B1). Immune cells express CYP27B1 and vitamin D3 receptors, and the expression of these receptors is regulated by immune signaling. Bottom Line: Vitamin D plays a vital role in the immune system. Low serum 25 (OH) D3 levels are associated with autoimmune and cardiovascular disease, cancer, and respiratory infections. In addition, vitamin D3 is essential for the cells of the respiratory epithelium. It confirms that the cells of the respiratory epithelium are constantly expressing CYP27B1.

Vitamin D is essential for antiviral immunity. Upon encountering viral nucleic acids, pattern recognition receptors are activated. That results in increased expression of the vitamin D receptor and CYP27B1. In addition, it makes the conversion of circulating vitamin D into its active form more intense. Conclusion: Vitamin D metabolism is associated with pathogen recognition and is an integral part of the innate immune response.

Laboratory tests confirm this:

  • Activation of TLR4 by endotoxin leads to increased expression of CYP27B1 in monocytes.
  • Activation of TLR4 or TLR3 triggers the expression of CYP27B1 in dendritic cells, altering the migratory properties of these cells to provide antigen presentation to T lymphocytes.
  • In human tracheobronchial epithelial cells, TLR stimulation increases the expression of CYP27B1. In addition, it leads to increased vitamin D3 into its active form and increased expression of antimicrobial peptides with antiviral action.

If circulating vitamin D levels are sufficient, activation of the TLR upon infection by the respiratory virus leading to the secretion of cytokines increases calcitriol levels, optimizing the immune response to fight the virus.

Research confirms this:

  • Cytokines IFN-γ, IL-13, IL-15, IL-4, IL-1, IL-2, and TNF-α regulate the expression of CYP27B1 and the metabolism of vitamin D. The signaling pathways involved in this process are the same as and when TLR is activated.
  • Vitamin D is required for the IFN-γ-dependent antimicrobial immune response of human macrophages against Mycobacterium tuberculosis.

To enter the cell, SARS-CoV-2 binds to ACE2. However, the assumption that high expression of ACE2 is harmful is incorrect. ACE2 confronts the acute respiratory distress syndrome and lung damage associated with COVID-19. The binding of SARS-CoV-2 to ACE2 decreases the activity of ACE2, which increases the activity of ACE1. It narrows the blood vessels in the lungs, which aggravates the severity of COVID-19. Vitamin D increases the expression of ACE2 in the lungs. It prevents pulmonary vasoconstriction in COVID-19 and reduces lung damage.

Clinical researches

  • Vitamin D3 supplementation (1000 or 2000 IU / day) increases the efficacy of antiviral treatment with pegylated interferon and ribavirin (PEG-IFN / RBV) in patients with hepatitis C.
  • Low serum vitamin D3 concentrations are associated with severe liver fibrosis and/or less responsiveness to PEG-IFN / ribavirin treatment.

Glutamine

Glutamine is a nitrogen source for rapidly dividing cells. Among these cells are lymphocytes, which need glutamine for nucleotide synthesis and energy production. T-lymphocytes are quickly activated after interacting with pathogens. Therefore, it requires a lot of energy and intensive biosynthesis.

Glutamine affects the immune response:

  • It is required for the division of T-lymphocytes. Therefore, the lack of glutamine impairs the function of T-lymphocytes.
  • Glutamine is required for activated T-lymphocytes for the production of IFN-γ and IL-2.
  • Lack of glutamine impairs antiviral defense. When faced with a virus, a naive T-lymphocyte changes its functions. It can become an effector T-lymphocyte, which enhances the immune response (helper T-cell, Th1), or become a regulatory T-lymphocyte, suppressing immune responses. What functions the T-lymphocyte will acquire depends on cytokines and the availability of glutamine.
  • Even in the presence of cytokines, which usually promote the formation of Th1 cells, the lack of glutamine leads to the formation of regulatory T-lymphocytes, suppressing the antiviral response.

Taking glutamine inhibits the replication of the herpes virus. Studies have shown that mice treated with glutamine showed lower viral levels, higher numbers of active helper and killer T cells in the spleen, and increased levels of IFN-γ in the vaginal fluid. These are signs of clinical improvement. In contrast, glutamine deficiency increased the replication of the herpes virus.

In another study, American scientists using bioinformatics technologies have calculated that glutathione and its precursor glutamine can prevent SARS-CoV-2 from entering cells and suppress altered gene expression associated with coronavirus.

Clinical researches

  • Low plasma glutamine levels are associated with poor clinical outcomes in ICU patients. After trauma and surgery, glutamine concentration in plasma and muscles is reduced, and T-lymphocytes acquire immunosuppressive properties. These changes increase the risk of infectious complications: pneumonia, sepsis, and bacteremia. Glutamine-enriched nutrition increases plasma glutamine concentrations and decreases the incidence of infectious complications in severely traumatized patients.
  • Glutamine restores the ability of T-lymphocytes to an immune response. In patients with severe trauma, activated T-lymphocytes showed low IFN-γ production – trauma suppressed the immune response. Conversely, glutamine supplementation increased IFN-γ production and promoted IL-4 average output.
  • A Cochrane systematic review and meta-analysis of 57 clinical trials in patients with serious illnesses or undergoing major surgery found that glutamine supplementation reduced the risk of infectious complications by 21%. In addition, taking glutamine reduces the average length of hospital stay and mechanical ventilation by 3.46 and 0.69 days, respectively.

Omega-3

Scientists from the Cedars-Sinai Medical Center (USA) and the Fatty Acid Research Institute (USA) investigated how omega-3 levels affect morbidity and mortality from COVID-19.

One of the causes of the severe and fatal COVID-19 is an increase in the inflammatory cytokines TNF-alpha, IL-1β, and IL-6, which leads to a cytokine release syndrome or cytokine storm.

Scientists evaluated the omega-3 index (O3I) in 100 patients with COVID-19. O3I – the level of polyunsaturated fatty acids EPA and DHA in erythrocytes. The researchers found that patients with an O3I ≥ 5.7% had a 75% lower risk of dying from COVID-19 than patients with a lower O3I.

Omega-3 (DHA and EPA), found in fish oil, reduce inflammatory responses and reduce the release of inflammatory cytokines:

Clinical Researches

An international team of scientists conducted a meta-analysis of treatment results in 1,280 patients with COVID-19 in the intensive care unit with acute respiratory distress syndrome. In patients receiving omega-3, blood oxygenation rates significantly improved, and the duration of stay in the intensive care unit and a ventilator was reduced.

For a review of research on the anti-inflammatory effects of omega-3s in COVID-19, see Omega-3 Fatty Acids Protect Against COVID-19.

Output

OncoTherad, which is used to treat non-muscle invasive bladder cancer, accelerates recovery from COVID-19. The reason for this is the amplification of interferon signals. Zinc, vitamin D3, and glutamine also improve the antiviral response of interferon. The combination of these drugs can effectively suppress SARS-CoV-2.

Omega-3 polyunsaturated fatty acids have anti-inflammatory effects and reduce the risk of complications and death from COVID-19. Omega-3 fatty acids can be increased by increasing your intake of oily fish, which are rich in EPA and DHA, or by taking omega-3 supplements.

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