A review was done to now the evidence for the antiviral and immunomodulatory properties of micronutrients. A search was done in Pubmed, Scopus, and Google Scholar for the nutrients with proven effect against viral infection. Experimental studies, clinical studies, reviews, and meta-analyses were studied descripitively.
Entry, replication, and immune response:
The S protein of coronavirus binds to angiotensin-converting enzyme 2 (ACE2) receptor of host cell4. The viral RNA[ribonucleic acid] enter into the host cell. The proteins are translated. The assembly and budding occur in theendoplasmic reticulum and Golgi compartment. Virions are then released from the infected cell through exocytosis. The antiviral drugs target the steps of this process.The macrophages present coronavirus antigens to T cells5. T cell activation produces cytokines. The cytokines amplify immune response. Interferons(IFN) limit virus spread, and promote macrophage phagocytosis of antigens. The CD8 cytotoxic T cells kill the infected cells. The B cells produce antibodies against the virus.
Experimental evidence:
Atherton et al exposed chick embryo tracheal organ cultures to ascorbic acid6. Increased resistance to infection by coronavirus was observed. An animal study by Jee et al. has shown that a diet high in vitamin A boosted the production of immunoglogulin G(IgG) in calves injected with bovine coronavirus7. Research has shown that vitamin D stimulates genetic expression of antimicrobial peptides such as defensins and cathelicidins in human monocytes, and neutrophils8. They have antiviral activity. Animal studies have shown that vitamin E increases lymphocyte proliferation, immunoglobulin levels, natural killer (NK) cell activity, and interleukin (IL)-2 production9. A study in healthy individuals showed that repletion of vitamin B6 resulted in decreased lymphocyte and interleukin-210. Folic acid deficiency results in atrophy of thymus and spleen, and decreased circulating T lymphocytes in animals11. Vitamin B12 administration increases CD8 and NK cells12.
Zinc inhibited the replication of SARS-CoV in cell culture study13. Supplementation with selenium has been shown to cause increase in the activity of cytotoxic lymphocytes and NK cells14. A study in aged mice has shown that dietary selenium increased the ability of splenic lymphocytes to undergo blastogenesis15. Iron deficiency impairs cell-mediated and innate immunity16. The T cell proliferation on stimulation is only 40–50% in iron-deficient women, compared to iron-sufficient women. A murine cell line study demonstrated that magnesium induced macrophages to produce the cytokines interleukin (IL)-4 and IL-1017. Cell culture studies have shown that a decline in copper status decreases IL-2 production by activated human T-cells18.
Control of inflammation:
The antioxidants like vitamin C and vitamin E can help in controlling the pro-oxidative state known as a ‘cytokine storm’, produced by excessive inflammation11. Intravenous vitamin C is being investigated as a treatment for cytokine storm syndrome19. Selenium has been shown to moderate the inflammatory responses, and restore the antioxidant capacity of the lungs in patients with acute respiratory distress syndrome (ARDS)20. Zinc has protective effects on the lungs in patients receiving mechanical ventilation for ARDS21. Vitamin D can reduce the expression of pro-inflammatory cytokines and increase anti-inflammatory cytokines22.
The results of the review are tabulated (table-1).
Table 1
Effect of micronutrients on the immune system.
Micronutrient
|
Observed effect
|
Vitamin C
|
Increased resistance to infection by coronavirus.
Has antioxidant effect.
|
Vitamin A
|
Boosts the production of immunoglobuilin G.
|
Vitamin D
|
Stimulates the expression of antimicrobial peptides such as defensins and cathelicidin.
Increases the anti-inflammatory cytokines.
|
Vitamin E
|
Increases lymphocyte proliferation, natural killer cell activity, immunoglobulin level, and interleukin-2 production.
Has antioxidant effect.
|
Vitamin B6
|
Needed for lymphocyte and interleukin-2.
|
Folic acid
|
Needed for thymus, spleen, and circulating T lymphocytes.
|
Vitamin B12
|
Increases CD8 and natural killer cells.
|
Zinc
|
Inhibits the replication of SARS-CoVirus.
Has protective effect on the lungs.
|
Selenium
|
Increases the activity of cytotoxic lymphocytes and natural killer cells.
Restores the antioxidant cpacity of the lungs.
|
Iron
|
Necessary for T cell proliferation.
|
Magnesium
|
Induces the production of interleukin-4 and interleukin-10.
|
Copper
|
Needed for the production of interleukin-2.
|
Current guidelines:
The European Food Safety Authority (EFSA) has endorsed 10 micronutrients as essential for healthy maintenance of the immune system: vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, folate, zinc, iron, copper, and selenium23. There are several trials ongoing involving vitamins A, C, D, and E, and micronutrients magnesium, and zinc against coronavirus disease-19 (COVID-19), registered by the world health organization (WHO)24. There are many meta-analyses on the randomized controlled trials (RCT) about the effect of micronutrients on viral infection25.The analyses of the trials supplementing vitamin C, vitamin D, vitamin E, and selenium have shown significance. Han et al did a pilot study of high dose vitamin D administration in ventilated intensive care unit patients26. It was found that high-dose vitamin D3 was associated with decreased the length of hospital stay.
Safety of supplementation:
There are concerns about the adverse effects of vitamin and mineral supplementation27. It has been found in systematic review that the use of multivitamins and minerals within the range of the dietary reference intake will not result in excess intake28. The American and European boards have defined the Tolerable Upper Intake Levels (UL) of vitamins and minerals to avoid the adverse health effects29.There are micronutrient supplementation programmes in developing countries for at-risk groups30. Examples are vitamin A supplementation for children and iron and folic acid for pregnant women31.