








key: cord-263749-bbhh5xb1
authors: Larenas-Linnemann, Désirée; Rodríguez-Pérez, Noel; Arias-Cruz, Alfredo; Blandón-Vijil, María Virginia; Del-Río-Navarro, Blanca E.; Estrada-Cardona, Alan; Gereda, José E.; Luna-Pech, Jorge A.; Navarrete-Rodríguez, Elsy Maureen; Onuma-Takane, Ernesto; Pozo-Beltrán, César Fireth; Rojo-Gutiérrez, María Isabel
title: Enhancing innate immunity against virus in times of COVID-19: trying to untangle facts from fictions
date: 2020-10-09
journal: World Allergy Organ J
DOI: 10.1016/j.waojou.2020.100476
sha: 
doc_id: 263749
cord_uid: bbhh5xb1

Introduction In the light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from the first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. Methods Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions in: 1) lifestyle related (exercise, >7 hours sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod) and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, i.e.). Results For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end a summary table demonstrates the best trials supporting (or not) clinical evidence. Conclusion Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.

context of the COVID-19 pandemic, extrapolated evidence from previous studies shows that regular, 128 moderate to vigorous exercise improves immune competency across the lifespan and may help to 129 reduce the frequency of upper-respiratory tract infections (URTIs).(9, 10) Importantly, this has been 130 observed also in older individuals (>65 year-olds) who regularly exercise, whose URTIs incidence per 131

year has been inversely associated with the energy expenditure utilized during physical activity. Conversely, some studies report that during prolonged periods of strenuous exercise (like marathons) 155

and after approximately 2 weeks following intense competitions, there is an immunodepression span 156

(the "open window" period), related to a higher rate of URTI-like symptoms (mainly self-reported) vs. 157 those who undergo lower physical activity. (21, 22) This theory, attributed to the consequences of 158 psychological stress and excessive training,(23, 24) is however highly debated today in the light of a 159 better understanding of the variability in the intensity-related response to physical activity, which 160 depends largely on the functional capacity of the immune system, so up-to-date perceptions on this 161 topic tend to discard the concept of exercise-induced immunosuppression. In fact, it is widely accepted 162 that, when performed regularly, during and after exercise the immune system is in a heightened state of 163 immune surveillance and regulation.(25) 164

During the COVID-19 quarantine it is important to stay active and to exercise regularly (gradually 165 increasing intensity), not only as a way to keep a healthy lifestyle, but also as an immunoprotective and 166 immunoregulatory activity. It is possible that the older adults (who are at higher risk of a severe SARS-167

CoV-2 infection) may obtain the greatest exercise-induced benefits to their immunological health. 168 169 2.2. Forest bathing (Shinrin Yoku) 170 In a series of several, subsequent small studies, Japanese investigators in cooperation with experts from 171 the Stanford University have shown that walking in a forest seems to enhance NK cell activity, partly 172 stimulated by volatile substances produced by trees (particularly phytoncides: antimicrobial essential 173 oils from trees). The first experiment showed in vitro that phytoncides activate NK cell activity and 174 augment NK cell granules content.(26) Then they confirmed this in peripheral blood lymphocytes of 175 subjects submitted to a prospective trial of a 3-day, 2-night trip to the forest including three 2-hour 176 walks.(27) In a third case-control trial they demonstrated that the effect was not related to the walking 177 J o u r n a l P r e -p r o o f 8 tour, as they compared the rise in NK-cell activity after a 3-day tour to a small city with that after a 3-day 178 tour to the forest. Both tours included three 2-hour walks, but NK-cell activity was only enhanced after 179 the forest trip. Moreover, NK-cell activity stayed elevated one week and still somewhat 30 days after the 180 tour. ( Other studies have shown that sleep deprivation, both complete or only selective to the rapid eye 198 movement (REM) stage, modifies various components of the innate immune system, such as dendritic 199 cells (DCs) and the percentage of some subpopulations of T cells (CD4+, CD8+ and NK) and cytokine 200 levels (IFN-γ, TNF-α and IL-1).(32-34) Specifically, in a clinical study in women 77 hours of sleep 201 deprivation (total and REM phase) resulted in a proinflammatory state and affected the cellular immune 202 response, presenting changes in the production of IFNs and in the phagocytic activity. Sleep deprivation 203 also decreased lymphocytic blastogenesis, NK cell activity, and regulation of IL-1 and IL-2.(35) 204 J o u r n a l P r e -p r o o f 9 Moreover, in the elderly, a sleep pattern with poor quality (self-reported) was related to increased levels 205 of IL-6 and this association was not explained by other factors, such as depressive symptoms, stress or 206 loneliness, but exclusively by sleep disturbance as an independent factor.(36) 207

As for the clinical evidence, an adequate sleep pattern also appears to be beneficial in modulating the 208 adaptive immune response. Spiegel The previously mentioned interventions are potential options that could improve the immune system 303 against SARS-CoV-2, but more evidence is required.(70) See table 2. 304

Zinc is an essential trace element for the proper functioning of multiple biological processes within the 306 human body, and its contribution to immunity is not an exception.(72) 307

The complete mechanism by which zinc could decrease the number or severity of viral infectious 308 processes in general and of COVID-19 in particular is not exactly understood yet; however, effects have 309 been observed on the binding of the viral agent to the mucosa and on its replication, as well as on the 310 regulation of the inflammatory process;(73) enhanced benefits have been hypothesized when co-311 administered with other medications such as (hydroxy)chloroquine that could function as a ionophore, 312 facilitating the entrance of zinc into the cells.(74) The human body's ability to store zinc is known to be 313 low; its deficiency compromises the immune system, as has been evidenced occasionally by thymic 314 atrophy, lymphopenia and altered lymphocyte responses. is not rock-solid yet, could be considered options that might help enhance the innate immune system 604 and thus worthwhile, especially, as most lack the risk for serious adverse events. Together with the 605 techniques focusing on reduction of the viral load, such as social distancing, equipment for personal 606 protection and adequate hand hygiene, improving our first-line defense seems vital. Finally, we add in 607 Exercise Regular exercise has a probable immunoprotective and immunoregulatory effect.

Older adults may obtain the greatest exercise-induced benefits for their immunological health.

Forest walks might be beneficial to boost innate immunity, particularly in times of a pandemic; evidence is limited, but there are no direct health-related safety issues.

The potential benefit of adequate sleep patterns overweighs the low level of evidence available up to date Mindfulness A constant program of a professionally guided meditation strategy could be beneficial to achieve an effective stress reduction and probably to reduce the burden of URTIs, mainly in older adults

The published study results so far have not been conclusive.

Subjects with vitamin deficiency would likely benefit most from supplementation.

The intervention could be considered relatively safe

A Cochrane collaboration systematic review showed daily doses of 0.2mg reduced the duration of common cold. In ARDS patients very high IV doses might be beneficial. More data are needed.

All 4 meta-analyzes have reported beneficial effects of zinc supplementation in children for the prevention of pneumonia. Important to restore the redox balance.

Adverse effects are considered mild 

A modest efficacy of some probiotics (Lactobacillus and Bifidobacterium strains) was found in reducing the incidence and duration of viral respiratory infections

Though it might seem of benefit, evidence of the reduction of infections is very scarce and quality trials are lacking.

With the use of Pidotimod there is a lower recurrence of respiratory tract infections as compared to conventional treatment and less use of antibiotics

We encourage to wait for the results of the ongoing RCT before using BCG vaccination for the prevention of COVID-19

Hetero-

The immune stimulation produced by heterologous vaccines enhances the response to other pathogens, different from the one in the vaccine and was associated with reduced all-cause infant mortality (e.g. measles vaccine, BCG).

Influenza: the once and future pandemic

Estimation of the basic reproduction number, average incubation time, 615 asymptomatic infection rate, and case fatality rate for COVID-19: Meta-analysis and sensitivity analysis

Preliminary prediction of the basic 618 reproduction number of the Wuhan novel coronavirus 2019-nCoV

SARS coronavirus pathogenesis: host innate immune responses and viral 620 antagonism of interferon

COVID-19: consider 622 cytokine storm syndromes and immunosuppression

Is a "Cytokine Storm" Relevant to COVID-19?

Targets of T Cell 626 Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Therapeutic Potential of B-1a Cells in COVID-19

Moderate to vigorous 630 physical activity and risk of upper-respiratory tract infection

Physical activity, 632 stress, and self-reported upper respiratory tract infection

The symptomatology of upper respiratory tract 634 infections and exercise in elderly people

Exercise and the aging 636 immune system

Moderate Exercise Enhances the Production of 638 Interferon-gamma and Interleukin-12 in Peripheral Blood Mononuclear Cells

Acute exercise 641 mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype

Exercise-induced redistribution of T 644 lymphocytes is regulated by adrenergic mechanisms

T-regulatory cells exhibit 646 a biphasic response to prolonged endurance exercise in humans

Exercise and psychosocial factors 649 modulate immunity to influenza vaccine in elderly individuals

Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory 653 Syndrome Coronavirus Infection

Influence of 655 exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4

Exercise amelioration of depression-like behavior in OVX mice 658 is associated with suppression of NLRP3 inflammasome activation in hippocampus

Does exercise increase the risk of upper respiratory 664 tract infections

Exercise, infection, and immunity

Exercise and airway injury in athletes

Debunking the Myth of Exercise-Induced Immune Suppression: 669 Redefining the Impact of Exercise on Immunological Health Across the Lifespan

Phytoncides (wood 672 essential oils) induce human natural killer cell activity

Forest bathing enhances 675 human natural killer activity and expression of anti-cancer proteins

Visiting a forest, but not 678 a city, increases human natural killer activity and expression of anti-cancer proteins

Effect of phytoncide 681 from trees on human natural killer cell function

Using psychoneuroimmunity against COVID-19

Galphas-684 coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells

Number and function of circulating human antigen 687 presenting cells regulated by sleep

REM sleep deprivation in rats results in 689 inflammation and interleukin-17 elevation

Effects of acute and chronic sleep loss on 691 immune modulation of rats

The Bidirectional Relationship between Sleep and Immunity 694 against Infections

Sleep disturbance and 696 older adults' inflammatory responses to acute stress

Effect of sleep deprivation on response to immunization. 698

Sleep habits and susceptibility to the 700 common cold

Behaviorally Assessed Sleep and Susceptibility 702 to the Common Cold

Psychological stress and susceptibility to the common cold

Relationships between mindfulness practice and levels of mindfulness, 706 medical and psychological symptoms and well-being in a mindfulness-based stress reduction program

Meditation or exercise for 709 preventing acute respiratory infection: a randomized controlled trial

Epidemic influenza and 711 vitamin D

Vitamin D and the intracrinology of innate immunity

The interplay between vitamin D and viral 715 infections

Vitamin D in allergic disease: shedding light on a complex problem

Unexpected actions of vitamin D: new perspectives on the regulation of 719 innate and adaptive immunity

Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. 722 Nutrients

Administration in Ventilated Intensive Care Unit Patients: A Pilot Double Blind Randomized Controlled 725 Trial

Vitamin D and Respiratory Tract 727 Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Vitamin D 730 supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of 731 individual participant data

Effect of Vitamin D3 Supplementation on 733 Respiratory Tract Infections in Healthy Individuals: A Systematic Review and Meta-Analysis of 734 Randomized Controlled Trials

Vitamin D supplementation for the prevention 736 of childhood acute respiratory infections: a systematic review of randomised controlled trials

The 2011 report on 739 dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need 740 to know

Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes 745 Endocrinol

Vitamin D: deficiency, sufficiency and toxicity

Intravenous Vitamin C for reduction of cytokines storm in Acute Respiratory 749 Distress Syndrome

Vitamin C Is an Essential Factor on the Anti-viral 751

Immune Responses through the Production of Interferon-alpha/beta at the Initial Stage of Influenza A 752 Virus (H3N2) Infection

Vitamin C and common cold-induced asthma: a systematic review and statistical 754 analysis

Acid Potentially Regulates Immune and Inflammatory Response Associated 757 with Coronavirus Infections: A Perspective from System Biology Analysis

Hypovitaminosis C and 759 vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit 760 Care

Functional Role of 763 Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work

Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Modulation of host defence 768 against bacterial and viral infections by omega-3 polyunsaturated fatty acids

Flavonoids from Houttuynia cordata attenuate 771 H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling

Individual risk management 774 strategy and potential therapeutic options for the COVID-19 pandemic

The clinical benefits of Chinese patent 776 medicines against COVID-19 based on current evidence

Traditional Chinese Medicine in the Treatment of 778

CoV-2): A Review and Perspective

Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic 781 agent for COVID-19

The Role of Zinc in Antiviral Immunity

Zinc and 785 respiratory tract infections: Perspectives for COVID19 (Review)

Improving the efficacy of Chloroquine and Hydroxychloroquine against 787 SARS-CoV-2 may require Zinc additives -A better synergy for future COVID-19 clinical trials

Zinc in human health: effect of zinc on immune cells

Role of zinc administration in prevention of childhood diarrhea 791 and respiratory illnesses: a meta-analysis

Low zinc status: a new risk factor for pneumonia in the 793 elderly?

Prevention of diarrhea and 795 pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized 796 controlled trials. Zinc Investigators' Collaborative Group

Zinc supplementation for the prevention of acute lower 798 respiratory infection in children in developing countries: meta-analysis and meta-regression of 799 randomized trials

Zinc lozenges may shorten the duration of colds: a systematic review

Fever and the thermal regulation of immunity: the immune 803 system feels the heat

Fever-like thermal conditions 805 regulate the activation of maturing dendritic cells

Conservation of 807 IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress

From fever to immunity: A new role for IGFBP-6?

Activation of the sympathetic nervous 814 system modulates neutrophil function

The regulation of interleukin-6 implicates skeletal muscle as an integrative 816 stress sensor and endocrine organ

Human monocyte stimulation by 818 experimental whole body hyperthermia

Functional expression 820 of TRPV channels in T cells and their implications in immune regulation

The acute phase 822 protein haptoglobin regulates host immunity

Passive heat therapy protects 826 against endothelial cell hypoxia-reoxygenation via effects of elevations in temperature and circulating 827 factors

Community-acquired pneumonia in the elderly: association of 829 mortality with lack of fever and leukocytosis

The effect of antipyretic 831 therapy upon outcomes in critically ill patients: a randomized, prospective study

The value of sanitarium treatment in respiratory diseases Washington, D.C.: Review and 836 Herald Publishing ASSN

Antipyretic drugs in patients with fever and infection: literature review

The effect of antipyretic 841 medications on mortality in critically ill patients with infection: a systematic review and meta-analysis

Population-level effects of suppressing fever

Therapeutic targeting of trained 846 immunity

BCG-induced trained 848 immunity in NK cells: Role for non-specific protection to infection

Trained immunity: A 852 program of innate immune memory in health and disease

Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 855 signalling pathways

MV140, a 857 sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human 858 dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88

Efficacy of whole-cell killed bacterial vaccines in preventing 864 pneumonia and death during the 1918 influenza pandemic

Sublingual therapeutic 866 immunization with a polyvalent bacterial preparation in patients with recurrent respiratory infections: 867 immunomodulatory effect on antigen-specific memory CD4+ T cells and impact on clinical outcome

Primary prevention of severe lower 870 respiratory illnesses in at-risk infants using the immunomodulator OM-85

Trained immunity in newborn 873 infants of HBV-infected mothers

Probiotics and the Gut Immune System: Indirect Regulation

Beneficial Effects of 877 Probiotic Consumption on the Immune System

Immunobiotic Strains Modulate Toll-Like Receptor 3 Agonist Induced Innate 879

Antiviral Immune Response in Human Intestinal Epithelial Cells by Modulating IFN Regulatory Factor 3 880 and NF-kappaB Signaling

Type I/II 882 Interferon in HIV-1-Infected Patients: Expression in Gut Mucosa and in Peripheral Blood Mononuclear 883 Cells and Its Modification upon Probiotic Supplementation

Prospective study of probiotic 885 supplementation results in immune stimulation and improvement of upper respiratory infection rate

Probiotics and Paraprobiotics in Viral Infection: 888 Clinical Application and Effects on the Innate and Acquired Immune Systems

Probiotics and COVID-19: one size does not fit all

Effectiveness of probiotics on the duration 893 of illness in healthy children and adults who develop common acute respiratory infectious conditions: a 894 systematic review and meta-analysis

Probiotics for preventing acute upper respiratory tract infections

Serum and 898 fecal profiles of aromatic microbial metabolites reflect gut microbiota disruption in critically ill patients: 899 a prospective observational pilot study

Is diet partly 901 responsible for differences in COVID-19 death rates between and within countries?

The cellular transfer of cutaneous hypersensitivity to tuberculin in man

CD8+ T cells produce a 906 dialyzable antigen-specific activator of dendritic cells

Immune Memory by Dialyzable Leukocyte Extract from a CD8+ T Cell Line

Early Differentiation of Human CD11c(+)NK Cells with gammadelta T Cell Activation Properties 912 Is Promoted by Dialyzable Leukocyte Extracts

Adjuvant treatment with a dialyzable leukocytes extract contributes to maintain 915 HPV-infected women free of low-grade cervical lesions

Dialyzable leukocyte extracts activate TLR-2 on monocytes

The dialyzable leukocyte extract Transferon(TM) inhibits tumor growth and brain 921 metastasis in a murine model of prostate cancer

Dialyzable Leukocyte Extract (Transferon) Administration in Sepsis: 924 Experience from a Single Referral Pediatric Intensive Care Unit

Innate Immune System to Improve Survival Traits in High Risk Pathogen Scenarios

Adjuvant treatment using transfer factor 929 for bronchogenic carcinoma: long-term follow-up

Immunostimulants in respiratory diseases: focus on Pidotimod

Effect of pidotimod on phagocytosis and 933 intracellular killing of Staphylococcus aureus by human circulating polymorphonuclear neutrophils and 934 alveolar macrophages

Pidotimod stimulates natural killer cell 936 activity and inhibits thymocyte cell death

Pidotimod Shows a Chemokine-Like Activity through CXC Chemokine Receptor 3 (CXCR3)

Pidotimod promotes 941 functional maturation of dendritic cells and displays adjuvant properties at the nasal mucosa level

Immunomodulatory effects 944 of pidotimod in adults with community-acquired pneumonia undergoing standard antibiotic therapy

Pidotimod, an immunostimulant in pediatric recurrent respiratory 947 tract infections: A meta-analysis of randomized controlled trials

Safety and Immunogenicity of Early 949

Bacillus Calmette-Guerin Vaccination in Infants Who Are Preterm and/or Have Low Birth Weights: A 950 Systematic Review and Meta-analysis

Treating BCG-induced disease in 952 children

Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis. Clin Infect 955 Dis

Early BCG-Denmark 957 and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

The efficacy of Bacillus Calmette-Guerin 960 vaccinations for the prevention of acute upper respiratory tract infection in the elderly

BCG 963 Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A 964 Randomized, Placebo-Controlled Pilot Study

BCG Vaccination Protects 966 against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with 967 Trained Immunity

BCG vaccine protection from severe coronavirus 969 disease 2019 (COVID-19)

SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young 971 Adults

BCG-induced trained immunity: can it offer protection against COVID-19? 973

Heterologous Immunity: Role in Natural and Vaccine-Induced Resistance to 975 Infections

Vaccination and heterologous immunity: 977 educating the immune system

Non-specific Effect of Vaccines: Immediate 979 Protection against Respiratory Syncytial Virus Infection by a Live Attenuated Influenza Vaccine. Front 980 Microbiol

Vitamin D supplementation and risk of respiratory tract infections: a meta-982 analysis of randomized controlled trials

Vitamin D supplementation for preventing infections 984 in children under five years of age

Effect of Vitamin C 986 Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis 987 and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial

Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of 991 Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence

Enteral omega-3 994 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. 998

days (enteral supplementation of n-3 fatty acids, γ-linolenic Rice

Unlike the normal anti-viral response with increased IFN type I and III and with it the activation of genes 1006 stimulated by IFN in adjacent cells and thereby increasing its anti-viral defense, the coronavirus has 1007 mechanisms that lower this anti-viral innate defense mechanism by interfering with IFN production and 1008 its effects. In addition, chemotactic molecules are released in a viral infection that attract macrophages 1009 (M∅), natural killer (NK) cells, and neutrophils. This reaction is not fully achieved during early infection 1010 with coronavirus, so the initial innate immune response appears incomplete and slow. After this first 1011 innate response, adaptive immunity is triggered via activation of dendritic cells (DC) that stimulate 1012 specific Th1 lymphocytes, which in turn activate cytotoxic T cells (Tccell) to eliminate infected cells, in 1013 the more advanced stages of the infection, along with plasma cell development and the production of 1014 antiviral IgM and IgG antibodies (not shown). However, in some patients with COVID-19 at this stage a 1015 dysregulated activation of macrophages (i.e. by IL6) is seen, causing the feared cytokine storm. 1016

The conversion of 25 OHD 2 to 1,25-(OH) 2 D 3 can be done directly in some cells of the immune system 1018 such as macrophages. The macrophage, like kidney cells, contains the enzyme 1-alpha hydroxylase that 1019 is capable of transforming Vitamin D into its active form, calcitriol. 1020Exposure of the macrophage to some pathogens induces the production of CP27B (step 1) (which allows 1021 25 OHD to enter the mitochondria for transformation into its active form 1,25-(OH) 2 D 3 ), (step 2) as well 1022 as vitamin D receptor (VDR) (step 3), which by binding to 1,25-(OH) 2 D3 increases the production of 1023 cathelicidin. (step 4) 1024The antimicrobial activity of vitamin D appears to be primarily dependent on the induction of 1025 cathelicidins, which perform numerous functions that enhance both innate and adaptive immunity; help 1026 improve the digestion process within the phagolysosome through a non-oxygen dependent mechanism 1027 

