








key: cord-322899-uxvlagt3
authors: Gorji, Ali; Ghadiri, Maryam Khaleghi
title: The potential roles of micronutrient deficiency and immune system dysfunction in COVID-19 pandemic
date: 2020-11-06
journal: Nutrition
DOI: 10.1016/j.nut.2020.111047
sha: 
doc_id: 322899
cord_uid: uxvlagt3

Preliminary studies indicate that a robust immune response across different cell types is crucial in the recovery from COVID-19. An enormous number of investigations point to the vital importance of various micronutrients in the interactions between the host immune system and viruses, including COVID-19. There are complex and multifaceted links between micronutrient status, the host immune response, and the virulence of pathogenic viruses. Micronutrients play a critical role in the coordinated recruitment of innate and adaptive immune responses to viral infections, particularly in the regulation of pro-and anti-inflammatory host responses. Furthermore, inadequate amounts of micronutrients not only weaken the immune system in combating viral infections, but also contribute to the emergence of more virulent strains via alterations of the genetic make-up of the viral genome. This study aimed to evaluate the evidence which suggests the contribution of micronutrients in the spread as well as the morbidity and mortality of COVID-19. Both the presence of micronutrient deficiencies among infected subjects and the effect of micronutrient supplementation on the immune responses and overall outcome of the disease could be of great interest to weigh the use of micronutrients in the prevention and treatment of COVID-19 infection. These investigations could be of great value in dealing with future viral epidemics.

Coronaviruses (CoV) are a large group of RNA viruses that primarily target the human respiratory system and can lead to a wide range of illnesses from the common cold to severe respiratory syndromes. In the last two decades, outbreaks of CoV-related infections, including the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome (MERS)-CoV, led to great public health problems and concerns. [1] A new coronavirus termed COVID-19 is currently associated with an increasing number and rate of morbidities and fatalities. The genetic analysis of the COVID-19 exhibited more than 50% sequence identity to MERS-CoV and 80% to SARS-CoV. [2] The innate immune system represents the first line of defense against viruses, which can inhibit virus replication, improve virus clearance, promote tissue repair, and activate a prolonged adaptive immune response against the viruses. [3] Viruses, such as CoV, could affect the function of the immune system in different manners, such as dysregulation of the macrophage antiviral response, induction of excessive cytokine-mediated immune system responses, and the activation of complement and coagulation cascades, which may result in enhanced infectivity and worse outcomes. [4] Since there is currently no effective drug or vaccine, boosting the immune system could be a reasonable option to combat COVID-19. A functional immune system is a prerequisite for the host's ability to prevent or limit viral infections. It is well-known that the nutrition of the host may influence the immune system and its susceptibility to viral infection. Numerous studies pointed to the increase in either susceptibility to or severity of various viral infections in the nutritionally deficient subjects. [5] In addition to the host's response, various micronutrients can have a significant influence on disease severity via the modulation of viral pathogenesis, such as mutations in the viral genome. [6] On the contrary, a viral pathogen in the micronutrient deficient population could replicate to a new, more pathogenic strain. [7] The objective of this review was to provide a collection of evidence points to the key role of various micronutrients on the interactions between the host immune system and viruses, particularly coronaviruses. Furthermore, we describe the evidence that may support the contribution of micronutrient deficiency and immune system dysfunction to the viral outbreaks, including COVID-19.

References for this review were identified through searches of PubMed for articles published from January 1961 to April 2020, by use of the terms "coronavirus", "immune system", "micronutrients", "vitamin", and "COVID-19". Relevant articles were identified through searches in Google Scholar and Springer Online Archives Collection. Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles indicate a strong link between viral infections; particularly CoV infection, with micronutrients and the immune system were selected. Articles published in English and Spanish were included.

The recruitment of various immune cells, including antibody-secreting cells and follicular helper T cells as well as activated CD4 + and CD8 + T cells, along with IgM and IgG COVID-19-binding antibodies have been reported in a patient with non-severe COVID-19. [8] In the initiation stage of severe COVID-19, increased amounts of pro-inflammatory cytokines and chemokines, like interleukin-2 (IL-2), IL-6, granulocyte-colony stimulating factor, interferon (IFN) γ-induced protein 10, monocyte chemoattractant protein-1, vascular endothelial growth factor, macrophage inflammatory protein-1α, and tumor necrosis factor-α (TNF-α), as well as lymphopenia have been detected in the serum of some patients. However, infection with COVID-19 in its critical stage exacerbates the secretion of T-helper-2 (Th2) cytokines, such as IL-4, IL-1RA, and IL-10, which suppress the inflammatory response [9, 10] . The preliminary data indicate the ability of the immune system to recognize COVID-19 and initiate an effective immune response across different cell types leading to successful recovery from the infection in cases with mild-to-moderate symptoms.

The majority of subjects with Covid-19 only have mild-to-moderate symptoms. However, the cytokine storm aggravates the infection severity and worsens prognosis. [9, 10] Poor outcomes with enormously high values of pro-inflammatory cytokines have been also reported in patients infected with MERS-CoV and SARS-CoV. [11] In addition, it has been suggested that a significantly elevated amount of platelets in patients with COVID-19, which is associated with a longer average hospitalization and poor prognosis, may be stimulated by the higher inflammatory cytokine levels. [12] Baseline total lymphocytes were significantly higher in survivors than non-survivors. In survivors, lymphopenia improved during hospitalization, whereas severe reduction of lymphocytes continued to decrease until death in non-survivors. The values of serum ferritin and IL-6 were markedly greater in non-survivors than survivors. [13] Due to the supporting role of micronutrients on the host immune responses to viral infections   (table 1) , it is not surprising if micronutrient deficiency would be associated with a weakened immune system and a higher risk for the occurrence and severity of viral infections.

Zinc homeostasis is essential for sustaining proper immune function. [14] Zinc plays an important role in host-virus interactions due to its effect on nucleic acid synthesis and repair, apoptosis, inflammation, and redox homeostasis. [15] Zinc baseline level is a crucial factor that can affect antiviral immunity, especially in zinc-deficient populations. [16] Zinc deficiency is associated with impaired immune responses and leads to a higher risk of respiratory viral infections, particularly in elderly subjects. [17] Zinc is involved in the modulation of the pro-inflammatory response by targeting nuclear factor Kappa B (NF-κB).

Zinc deficiency enhances the production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, and reduces the lytic activity of natural killer (NK) cells. Furthermore, zinc deficiency leads to a decrease in antibody production via the alteration of the function and number of various immune cells. [14] The zinc-finger domain is found in various proteins encoded by the genome of different CoV, such as SARS-CoV [18] , and plays a key role in viral replication and transcription. [19] A specific mutation within the zinc-finger domain of CoV caused reduced antiviral response.

[20] Disruption of the zinc-binding function of CoV-229E nonstructural protein-13 (nsp13) or deletion of the entire zinc-binding domain affects both transcription and replication of CoV.

[21] Furthermore, it has been shown that the zinc-binding domain may start to unfold during the first transition of SARS-CoV and lead to a reduction in pathogen virulence. 

Selenium deficiency not only weakens the host immune system against viral infections but also leads to viral genome mutations from benign variants to highly pathogenic viruses. [4] Inadequate antioxidant protection against various mutating RNA viruses, including SARS-CoV, has been observed in subjects with blood selenium concentrations of less than 1 μM/L. 

Iodide modulates the transcriptional immune signature of human peripheral blood immune cells and induces greater cytokine and chemokine secretion, such as IL-6, IL-8, and IL-10.

[36] Iodide is found in the salivary glands, nasal mucosa, and lung secretions. [37] The sodium-iodine symporter, a plasma membrane glycoprotein that mediates active Iodide transport in different tissues, contributes to the oxidation of iodide in the lungs, which improves the antiviral respiratory defense system. [38] The oral intake of potassium iodide 

Copper is an essential nutrient for the development and maintenance of the human immune system. Copper is crucial for the generation and response of IL-2 to adaptive immune cells, the production of antibodies, maintaining intracellular antioxidant balance, and self-protection of immune cells. [41, 42] Copper deficiency can lead to increased viral virulence, decreased IL-2 level and T-cell proliferation, and reduced phagocytic ability. [43] Copper exhibits a potent antiviral property, possibly via binding electron donor groups on viral proteins or nucleic acids. [44] Copper antiviral effects may also due to the regulatory roles of copper on certain enzymes, which are critical for the function of various types of immune cells. [42, 43] In addition, activated macrophages accumulate copper within the phagosome to inactivate the pathogens. This event plays an important role in the control of pulmonary infections. [45] Intravenous copper administration results in a greater copper concentration in the lung [46] , promotes the anti-inflammatory forkhead box P3-positive T-cells. [59] Vitamin A deficiency leads to the reduced weight of the thymus, decreased lymphocyte proliferation, impaired Tcell-mediated response, and enhanced pathogen binding to respiratory epithelial tissues. [60] Vitamin A inhibits viral replication, promotes the immune response, and decreases morbidity and mortality of some viral infections. [61] The beneficial effects of vitamin A on morbidity and mortality of some viral infections, such as measles and HIV, could be due to increased antibody production and lymphocyte proliferation as well as enhanced T-cell lymphopoiesis. [62] Clinical investigations and in vitro studies have indicated that vitamin A is the main regulator of mucosal immunity and could affect immune responses to mucosal infections. levels as well as an enhancement of CD4 + /CD8 + ratio and TNF-α value. [41] There are several experimental and clinical studies indicating the antiviral effects of B vitamins. Patients with HIV suffered from a high prevalence of vitamin B1 deficiency.

Vitamin B1 affects HIV infection via non-genomic mechanisms, which may lead to beneficial effects in patients with HIV. [72] Vitamin B2 alone or in combination with UV light has a potent antiviral effect on a wide range of viruses, such as MERS-CoV. [73] Deficiencies in vitamins B6, B9, and B12 render people more susceptible to viral respiratory infections, such as influenza. [74] It has been suggested that a vitamin A-vitamin B6 conjugate analogue can exert an antiviral effect by regulating transcription and/or replication of various RNA viruses, including coronavirus. [75] Vitamin C A wide range of studies points to the importance of vitamin C in immune host responses to viral infections. Vitamin C promotes the production, function, and migration of immune cells, and enhances serum values of antibodies and complement proteins. [76] Vitamin C also supports the differentiation and proliferation of lymphocyte and enhances apoptosis, chemotaxis, and IFN production. [77] Clinical trials and experimental studies suggested that vitamin C inhibits the pro-inflammatory cytokines, like TNF and IL-6, and increases the proinflammatory cytokines, such as TNF, IL-6, and IL-1β. [78] Vitamin C exerts an antiviral immune response against the influenza virus via the enhancement of IFN-IL-1α/β production. [79] Vitamin C enhances the resistance of broiler chicks [80] and chick embryo tracheal organ cultures [81] to infections induced by an avian coronavirus. Vitamin C reduced the cytokine levels (TNF-α and IL-1β) in an animal model of acute respiratory distress syndrome (ARDS); suggesting its beneficial effect for the treatment of similar inflammatory disorders. [82] Indeed, the intravenous administration of vitamin C in patients suffering from sepsis and ARDS significantly reduced the mortality rate. [83] Several investigations have suggested that vitamin C in high dosages has direct virucidal effects. [84] Several clinical trials have shown a significantly lower incidence of RTI in vitamin C-treated subjects. [85] On the contrary, vitamin C deficiency enhances the risk of respiratory infections, particularly in the elderly. Vitamin D deficiency was associated with higher illness severity, multiple organ dysfunctions, and mortality in critically ill subjects, particularly with sepsis and pneumonia. 

Vitamin E supports the integrity of epithelial membranes and increases IL-2 production, NK cell activity, T-cell-mediated functions, and lymphocyte proliferation. Furthermore, vitamin E initiates T-cell activation, promotes Th1 proliferation, and inhibits Th2 response. [101] Vitamin E supplementation causes a higher IL-2 and IFN-γ production with a lower lung virus titer in animals with the influenza virus. [102] Vitamin E deficiency markedly increases the viral pathogenicity and heart damage in mice infected with Coxsackieviruses-B3. [103] Administration of Vitamin E increased lymphocyte proliferation as well as IL-2 and IFNγ production in healthy subjects and aged mice after influenza infections. [102] A modest level of vitamin E supplementation regulates the cellular free radical-antioxidant balance, enhances the antibody response, and activates the immune cells of broilers vaccinated with the infectious bronchitis virus. [104] H1N1-infected mice have shown positive associations between anti-inflammatory cytokine IL-10 level and vitamin E metabolism. [105] Vitamin E and selenium exhibit strong control over viral replication and mutation. In a nutritional deficiency condition of these micronutrients, RNA viruses are able to convert to more virulent strains. [106] Vitamin E deficient mice failed to exhibit an appropriate immune response to HSV-1 infection. [107] A significant increase in lung and serum vitamin E levels has been observed a few days after infection with the influenza virus in mice.

[108] Critically ill patients who were admitted to an ICU with ARDS have shown a significant reduction of vitamin E plasma level.

[109] The use of Vitamins E and C in critically ill patients reduced the incidence of ARDS and pneumonia and shortened ICU length of stay. [110] 

The most vulnerable groups to the severe-critical complications of COVID-19 are the elderly above the age of 60 and subjects with chronic diseases, including hypertension, diabetes, and cardiovascular or respiratory diseases. [111, 112] Although only 36% of patients infected with COVID-19 in Italy were over the age of 70, more than 80% of deaths occurred in people of this age.

[113] Furthermore, older adults are more susceptible to severe COVID-19 at admission. [114] Immune function in older adults can be modified by nutritional and pharmacological interventions. [115] Aging causes alterations in every component of the immune system, which leads to increased morbidity and mortality following infectious diseases. [116, 117] The altered function of the immune system in the elderly can be promoted via the manipulation of cytokine production, changes of metabolic pathways in immune cells, and immune-system rejuvenation aimed at reactivating the generation of new lymphocytes.

[118] Micronutrient interventions have shown a promising impact in targeting the immune system impairments observed in the elderly and improve the infection-related morbidity and mortality. [119, 120] Micronutrient deficiencies affect approximately two billion people worldwide and contribute essentially to the global burden of several diseases. [121] For instance, zinc deficiency affects approximately 30% of the world population with ranging from 4% to 73% across different countries and implicated in about 16% of lower RTI.

[122] Micronutrient deficiencies decrease the ability to resist infections and are common causes of immunodeficiency in the developing countries. [123] Although micronutrient deficiencies are one of the major public health challenges in developing countries, about 30% of the population in industrialized societies are also affected. [124] Silent epidemics of micronutrient deficiencies could be due to insufficient intake and/or sufficient intakes in association with impaired absorption owing to infection, inflammation, or chronic diseases. [123, 125] Approximately 35% of populations who are above the age of 50 in Europe, USA, and Canada have an obvious deficiency of one or more essential micronutrients. [126] In addition to an insufficient intake of micronutrients, older people lose their ability to produce endogenous antioxidants. [127] Italy, Spain, and France have experienced the highest COVID-19 death toll in Europe and the elderly in these countries have shown the highest prevalence of vitamin D deficiency compared with many other European countries. [128, 129] Approximately 60% of people who died from COVID-19

in Italy were living in the Lombardy region. During the cold seasons, up to 60-90% of the population in this region shows deficient/insufficient values of vitamin D. [130] The Lombardy region, the most air polluted area of Italy, has a high rate of hospitalizations and respiratory illnesses. [131] Air pollution associated with increased ozone values absorbs UVB radiation and leads to vitamin D deficiency. [132] The overall prevalence of low vitamin D status is above 40% in the US population. [133] Several clinical studies indicate the vital role of micronutrients in the prevention and treatment of viral infections. [134, 135] Micronutrient deficiencies, including zinc and vitamins B2, B6, B12, C, and D, were reported to be common in the Ecuadorian elderly, which weakened their immune system and placed them at greater risk of viral RTI. [74] Administration of Zinc and vitamin A significantly decreased the incidence of pneumonia in children with pneumonia [136] , and oral zinc supplementation could shorten the duration of symptoms of respiratory infection. [137] Food and Agriculture Organization of the United Nations has reported that nutrition and antiviral drugs are equal in the treatment of HIV infection and regular intake of micronutrients is crucial for promoting the immune response and maintaining good health for both infected and uninfected individuals. [138] Early administration of vitamin A reduced the mortality rate of patients with Ebola virus disease during the Western African outbreak. [139] Supplementation of micronutrients in elderly subjects enhanced the number of T-cells and lymphocytes, improved lymphocyte response to mitogen, increased IL-2 levels and NK cell activity, promoted the response to the influenza virus vaccine, and reduce the duration of viral diseases. [41, 140] Some commonly used drugs, such as antibiotics, can lead to various micronutrient depletions, such as iron and vitamins A, B, and D. [141] A combination of micronutrient supplementation in older adults may decrease antibiotic usage and causes a higher post-vaccination immune response. [126] Interestingly, some countries with higher morbidity and mortality of COVID-19, such as Italy and Spain, have a greater consumption of antibiotics compared to other European countries. [142, 143] Mice treated with antibiotics are unable to stimulate cytokine release in the lung and augment protective T-cell responses following influenza infection. [144] Infectious disease outbreaks could indeed be the result of infection by a virus whose virulence has altered as a result of replicating in a nutritionally deficient host so that a non-virulent virus becomes a pathogen due to changes in its genome. In addition, available data strongly suggest that the association of unpredictable occurrence of novel viral pathogens combined with decreased host immunity and micronutrient deficiency poses a twofold threat to human health in the near future. Further investigating the role of micronutrients and their substitution on immune system activity, therefore, may present a highly cost-efficient and uncomplicated measure with promising long-term benefits on future viral outbreaks. The development of novel vaccinations and drugs targeting pathogens that cause currently relevant diseases is often an expensive and risky process associated with a narrow spectrum efficacy due to their selective applications. Furthermore, the use of novel vaccines and drugs is usually restricted to the global population due to their high costs. A decade ago, the Copenhagen Consensus project on hunger and malnutrition concluded that efforts to provide micronutrients for the global population generate higher returns than any other public health measure. [147] There is no conflict of interest.

The authors received no financial support for this study. 

10 Years on, the world still learns from SARS

Transmission routes of 2019-nCoV and controls in dental practice

Coronavirus infections and immune responses

Molecular pathology of emerging coronavirus infections

Micronutrients and host resistance to viral infection

Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency

Host nutritional status and its effect on a viral pathogen

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical Features of 69 Cases with Coronavirus Disease

Expression of elevated levels of proinflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

Platelet-to-lymphocyte ratio is associated with prognosis in patients with Corona Virus Disease-19

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Zinc in Infection and Inflammation

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

The Role of Zinc in Antiviral Immunity

Serum zinc and pneumonia in nursing home elderly

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex

Mutagenesis of Coronavirus nsp14 Reveals Its Potential Role in Modulation of the Innate Immune Response

Crystal structure of Middle East respiratory syndrome coronavirus helicase

Differential domain structure stability of the severe acute respiratory syndrome coronavirus papain-like protease

Host nutritional status: the neglected virulence factor

A Role for Iodide and Thyroglobulin in Modulating the Function of Human Immune Cells

Extrathyroidal iodide concentrating mechanisms

The Na+/I-symporter (NIS): mechanism and medical impact

Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide

In Vitro Bactericidal and Virucidal Efficacy of Povidone-Iodine Gargle/Mouthwash Against Respiratory and Oral Tract Pathogens

Immune function and micronutrient requirements change over the life course

A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection

Copper and immunity

Deactivation of human immunodeficiency virus type 1 in medium by copper oxide-containing filters

The Yin and Yang of copper during infection

Pathogenesis of porcine reproductive and respiratory syndrome virus-induced increase in susceptibility to Streptococcus suis infection

Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Role of Vitamin A in the Immune System

Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influenza: A New Perspective. ISRN Infectious Diseases ID 246737

Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes

Vitamin-mediated regulation of intestinal immunity

High-dose dietary zinc oxide mitigates infection with transmissible gastroenteritis virus in piglets

Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine

Epithelia-damaging virus infections affect vitamin A status in chickens

Metabolism of Dietary and Microbial Vitamin B Family in the Regulation of Host Immunity

The effects of vitamin B on the immune/cytokine network and their involvement in depression

Vitamin B5 reduces bacterial growth via regulating innate immunity and adaptive immunity in mice infected with Mycobacterium tuberculosis

Effects of vitamin B6 deficiency on the composition and functional potential of T cell populations

Inflammation, vitamin B6 and related pathways

The role of thiamine in HIV infection

Inactivation of Middle East respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment

Micronutrient deficiencies are associated with impaired immune response and higher burden of respiratory infections in elderly Ecuadorians

A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-derived zinc-chelating trioxa-adamantane-triol

Vitamin C and immune cell function in inflammation and cancer

Vitamin C: an essential "stress hormone" during sepsis

Vitamin C and Immune Function

Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection

Ascorbic acid and infectious bronchitis infections in broilers

The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus

The Protection Potential of Antioxidant Vitamins Against Acute Respiratory Distress Syndrome: a Rat Trial

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial

The antiviral properties of vitamin C

Vitamin C and SARS coronavirus

Ascorbic acid role in containment of the world avian flu pandemic

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications

Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns

25-Dihydroxyvitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells

Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves

Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro

Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Evaluation of vitamin D endocrine system (VDES) status and response to treatment of patients in intensive care units (ICUs) using an online SPE-LC-MS/MS method

Oxidative stress in critically ill ventilated adults: effects of vitamin D3 and associations with alveolar macrophage function

Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection

Steroids as regulators of the mammalian immune response

Vitamin D and immune function

The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States

Association of vitamin D supplementation with respiratory tract infection in infants. Matern Child Nutr e12987

The Role of Vitamin E in Immunity

Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus

Vitamin E deficiency intensifies the myocardial injury of coxsackievirus B3 infection of mice

Relationship between the level of dietary vitamin E and the immune response of broiler chickens

Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates

The immune response to herpes simplex virus encephalitis in mice is modulated by dietary vitamin E

Effect of vitamin E supplementation on lipid peroxidation in blood and lung of influenza virus infected mice

E deficiency and lipoperoxidation during adult respiratory distress syndrome

Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients

Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis

Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis

Aging, Immunity, and Infection

Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity

Nutrition, diet and immunosenescence

Physiological role of antioxidants in the immune system

World Health Organization, Food and Agricultural Organization of the United Nations. Guidelines on food fortification with micronutrients

The interaction between nutrition and infection

Effects of widely used drugs on micronutrients: a story rarely told

Dairy products and inflammation: A review of the clinical evidence

Nutrition and the immune system from birth to old age

Effects of the association of aging and obesity on lipids, lipoproteins and oxidative stress biomarkers: A comparison of older with young men

A systematic review of vitamin D status in southern European countries

Nutritional challenges for older adults in Europe: current status and future directions

Association between solar ultraviolet doses and vitamin D clinical routine data in European mid-latitude population between

Air pollution exposure, causespecific deaths and hospitalizations in a highly polluted Italian region

Sunlight and Vitamin D: A global perspective for health

Zinc and selenium indicators and their relation to immunologic and metabolic parameters in male patients with human immunodeficiency virus

Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?

Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum

Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials

Combating Micronutrient Deficiencies: Foodbased Approaches

Vitamin A Supplementation Was Associated with Reduced Mortality in Patients with Ebola Virus Disease during the West African Outbreak

Influence of a complex micronutrient supplement on the immune status of elderly individuals

Drug-micronutrient interactions: food for thought and thought for action

High antibiotic consumption: a characterization of heavy users in Spain

Antibiotic Consumption and Resistance during a 3-Year Period in Sicily, Southern Italy

Microbiota regulates immune defense against respiratory tract influenza A virus infection

Cuban epidemic neuropathy. II. The antigenic characteristics of the viral isolates

Food supplementation among HIV-infected adults in Sub-Saharan Africa: impact on treatment adherence and weight gain

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

