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Key Words: vitamin D, innate immunity, respiratory infections, COVID-19, SARS-CoV-2, sunlight

Summary

Acute viral respiratory infections, including COVID-19, are strongly correlated with vitamin D insufficiency. They are also strongly seasonal, peaking in the winter, when the availability of the UVB component of sunlight is low. UVB is known for inducing production of vitamin D in the skin. However, vitamin D supplementation has shown little or no effect in the prevention of respiratory infections in adults. Thus, UVB light provides the immune system with essential benefits that are not produced by oral vitamin D supplements. 

This paper posits that UVB light stimulates production of cathelicidin and other antimicrobial peptides (AMPs) in the skin.  These AMPs are carried by the blood to the respiratory tract and enhance innate respiratory immunity. AMPs are also referred to as “natural antibiotics,” because they protect not only against microbes but also enveloped viruses, including influenza and coronaviruses.

The skin and respiratory tract surfaces play a similar role in the body – acting as a barrier between the body and the external world. Many of the same AMPs, including cathelicidin, are produced and act in the skin, the respiratory tract surface, the intestines, and some blood cells. Cathelicidin is carried by the blood.

This paper provides additional evidence that exposure to UVB in sunlight or artificial UVB sources, in safe amounts, depending on skin phototype (dark skin might need 5-6 times more exposure than light skin), is necessary for maintaining normal innate immunity. Vitamin D supplements cannot replace UVB exposure.

Intro

Infection Seasonality

Currently (at the end of November 2020), the increase in COVID-19 infections, in the northern hemisphere, matches seasonality expectations. COVID-19 is not an exception among respiratory infections. Its seasonality has been observed in both hemispheres. The inverse correlation between sunlight UV and SARS-COV-2 positivity [1] has been reported. The increase in COVID cases is happening slightly ahead of the regular flu season. A significant part of the population has had less than usual sunlight exposure in the previous months, due to COVID-19 precautions.

The seasonal character of influenza has been noted for long time [2]. This seasonality is linked to low exposure to the UVB (wavelengths 280-320 nm) component in sunlight, which results in insufficient levels of vitamin D. Among other effects, vitamin D is required for AMPs production, so the increase in the respiratory infections in winter was linked to seasonal impairment of the AMPs production [3]. In the US, respiratory infections boom in the winter and almost disappear in the summer and the death rate is 25% higher in the winter than in the summer [4]. Many observational studies have shown that moderate UVB exposure led to sharp decrease in respiratory infections [5][6] reports weekly inverse correlation between sunlight and spread of 2009 H1N1 zoonotic influenza virus (“swine flu”).

The lack of UVB exposure and low levels of vitamin D are strongly associated with each other and with a susceptibility to respiratory infections. The hypothesis that UVB exposure can be replaced with vitamin D supplementation, in order to maintain innate respiratory immunity, has somehow become entrenched.  This flawed belief continues to persist despite multiple studies in which oral supplementation with vitamin D has shown no or little respiratory immunity benefits [7].

Although common wisdom in mid latitudes of Europe held that moderate exposure to sunlight is beneficial [8], such research has not been encouraged [9].

Vitamin D

Vitamin D3 is produced by the skin when it is exposed to UVB light. It can also be also ingested with the food. Either way, it is inactive until metabolized in the liver to 25(OH)D (25-hydroxy-vitamin D). 25(OH)D then further metabolizes to 1,25(OH)2D3 (1.25‐dihydroxyvitamin D3) in the kidneys as well as many other organs, including the skin and epithelial cells of the respiratory tract.

Innate Immune System & AMPs

The human innate immune system responds to pathogens without the need to recognize them. This is in contrast to the adaptive immune system, which needs to recognize the particular pathogen, before counteracting it with antigens or T-cells.

This makes AMPs critically important in the defense against novel respiratory viruses, such as SARS-CoV-2, which are not recognized by the body. Cathelicidins and other AMPs are the tools of the innate immune response. Cathelicidins dissolve viral and microbial membranes, and also alert the rest of the immune system to act [10][11]. LL-37 (having precursor protein hCAP18) is the only known human cathelicidin. In the skin, cathelicidin serves as a chemical shield. Cathelicidins are produced from keratinocytes [17], in many tissues in the skin to epithelial cells of the lungs [12]. Some blood cells also produce AMPs.

Cathelicidin production in the skin is induced by UVB (as explained below), or by the local injury or infection [10].

Results

For a long time, it has been observed how rarely sunburns (severely damaging skin and suppressing adaptive immune system) lead to opportunistic infections.

When the skin is damaged, AMPs are produced. Their primary role is the local anti-microbial protection of the damaged skin, but they also travel in the blood [13] and can protect respiratory tract. LL-37 was shown to directly inhibit the influenza virus in humans [14].

In 2005, Mallibris et al. conducted a study, in which they exposed buttocks of eight volunteers to UVB [15]. The study summarized the results in the title “UVB Upregulates the Antimicrobial Protein hCAP18 mRNA in Human Skin.” One-time exposure of a single buttock to the minimal erythema dose of UVB led to 2.3x increase of hCAP18 level in the exposed skin, within 24 hours. This amount of UVB cannot significantly increase the body’s vitamin D levels. Thus, the production of extra hCAP18 was solely due to the UVB stimulation, not increased vitamin D levels.

Zasloff [16], concluded cautiously that sunlight “activates an arm of innate immunity within the skin.”  In addition to hCPA18/LL-37 production, Zasloff suggested a few other mechanisms.

Other experiments [17] with UVB successfully induced defensins and other universal AMPs in keratinocytes. This lead to the conclusion that UVB exposure increases local production of AMPs and boosts innate immunity [18].

In hindsight, it is not that surprising that the skin reacts to ultraviolet irradiation similarly to how it reacts to other stimuli, such as physical injury or infection.

UVB light might increase production of AMPs in the skin through increased local production of 1.25‐dihydroxyvitamin D from 25(OH)D. Cathelicidin and other AMPs, produced in the skin, travel in the blood to other parts of the body, including the epithelial surfaces of respiratory system, boosting innate respiratory immunity. It is also possible that UVB activates blood cells, passing through the exposed skin and capable of producing AMPs (neutrophils, macrophages, lymphocytes, etc.), and they produce AMPs in other tissues as well.

Vitamin D Supplementation does not noticeably increase LL-37 levels in the blood [19][20], even when it significantly increases 25(OH)D levels.

Discussion

[20] reported that a subgroup of the experiment subjects had ~20% increase of LL-37 concentrations, corresponding to 200% increase in 25(OH)D concentrations in the blood following ergocalciferol supplementation. This relation is insignificant, and might be explained by their initial deficiency of 25(OH)D and/or sunlight exposure, not known the to researchers

[19] demonstrated a decrease in sickness with supplementation. The supplementation was Vigantol – vitamin D3 dissolved in triglyceride. Multiple studies from 1930s demonstrated significant improvement of respiratory immunity from taking cod liver oil [5], which contained not only vitamin D, but also Omega-3 fatty acid, and vitamin A. The effect of combined vitamin D / Omega-3 supplementation is a promising avenue for research. A word of caution: some sources say that modern techniques of cod liver and other fish oil preparation remove most vitamin D.

[21] and [22]reported an inverse correlation between sunlight UV and COVID-19 mortality,. This might be due of the anti-inflammatory effect of vitamin D and is out of the scope of this paper.

Conclusions

Exposure to UVB in sunlight or artificial UVB sources, in proper amounts and adjusted by skin phototype (dark skin might need 5-6 times more exposure than light skin), is necessary for maintaining normal innate immunity. Vitamin D supplements do not produce the same benefits or immunity as UVB exposure. UVB stimulates production of cathelicidin and other AMPs in the skin and/or certain blood cells travelling through skin. These AMPs are carried by the blood to the respiratory tract surfaces and enhance innate respiratory immunity.

No Competing Interests

The author declares no competing interest.

No funding was provided for this work.

Acknowledgements

Thanks to AO for the contribution to this paper.

An author's remark
  1. I bent backward in order not to say that the ozone hoax is behind the suppression of the research on the UVB health benefits. Nevertheless, this article has been rejected by preprints.org.
  2. People who wear masks outside further decrease the amount of the beneficial UVB.
  3. The innate immunity is surprisingly rarely mentioned in the discussions of the response to COVID-19, but it is what protects most people from getting sick when from exposure to SARS-COV-2.

References

[1]       Tang L, Liu M, Ren B, Wu Z, Yu X, Peng C, et al. Sunlight ultraviolet radiation dose is negatively correlated with the percent positive of SARS-CoV-2 and four other common human coronaviruses in the U.S. Sci Total Environ 2021;751:141816. https://doi.org/10.1016/j.scitotenv.2020.141816.

[2]       CANNELL JJ, VIETH R, UMHAU JC, HOLICK MF, GRANT WB, MADRONICH S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129–40. https://doi.org/10.1017/S0950268806007175.

[3]       Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J 2008;5:29. https://doi.org/10.1186/1743-422X-5-29.

[4]       Grant WB, Bhattoa HP, Boucher BJ. Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. 19th Vitam Workshop 2017;173:5–12. https://doi.org/10.1016/j.jsbmb.2017.01.003.

[5]       Umhau J. Vitamin D and Influenza 2008.

[6]       Slusky DJG, Zeckhauser RJ. Sunlight and Protection Against Influenza. Econ Hum Biol 2020:100942. https://doi.org/10.1016/j.ehb.2020.100942.

[7]       Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583. https://doi.org/10.1136/bmj.i6583.

[8]       Goldstein M, Kagan B. Benefits of tanning (Personal Communication) 1980.

[9]       Lucas RM, Ponsonby A-L. Considering the potential benefits as well as adverse effects of sun exposure: Can all the potential benefits be provided by oral vitamin D supplementation? UV Expo Guid Balanc Approach Health Risks Health Benefits UV Vitam Proc Int Workshop Int Comm Non-Ioniz Radiat Prot Munich Ger 17-18 Oct 2005 2006;92:140–9. https://doi.org/10.1016/j.pbiomolbio.2006.02.019.

[10]    Schauber J, Gallo RL. The vitamin D pathway: a new target for control of the skin’s immune response? Exp Dermatol 2008;17:633–9. https://doi.org/10.1111/j.1600-0625.2008.00768.x.

[11]    Heilborn JD, Nilsson MF, Sørensen O, Ståhle-Bäckdahl M, Kratz G, Weber G, et al. The Cathelicidin Anti-Microbial Peptide LL-37 is Involved in Re-Epithelialization of Human Skin Wounds and is Lacking in Chronic Ulcer Epithelium. J Invest Dermatol 2003;120:379–89. https://doi.org/10.1046/j.1523-1747.2003.12069.x.

[12]    Bals R, Wang X, Zasloff M, Wilson JM. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci 1998;95:9541. https://doi.org/10.1073/pnas.95.16.9541.

[13]    Zanetti M. The Role of Cathelicidins in the Innate Host Defenses of Mammals. Curr Issues Mol Biol 2005. https://doi.org/10.21775/cimb.007.179.

[14]    Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol 2013;94:40–9. https://doi.org/10.1099/vir.0.045013-0.

[15]    Mallbris L, Wiegleb Edström D, Sundblad L, Granath F, Ståhle M. UVB Upregulates the Antimicrobial Protein hCAP18 mRNA in Human Skin. J Invest Dermatol 2005;125:1072–4. https://doi.org/10.1111/j.0022-202X.2005.23872.x.

[16]    Zasloff M. Sunlight, Vitamin D, and the Innate Immune Defenses of the Human Skin. J Invest Dermatol 2005;125:xvi–xvii. https://doi.org/10.1111/j.0022-202X.2005.23924.x.

[17]    Gläser R, Navid F, Schuller W, Jantschitsch C, Harder J, Schröder JM, et al. UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo. J Allergy Clin Immunol 2009;123:1117–23. https://doi.org/10.1016/j.jaci.2009.01.043.

[18]    Schwarz T. The Dark and the Sunny Sides of UVR-Induced Immunosuppression: Photoimmunology Revisited. J Invest Dermatol 2010;130:49–54. https://doi.org/10.1038/jid.2009.217.

[19]    Bergman P, Norlin A-C, Hansen S, Rekha RS, Agerberth B, Björkhem-Bergman L, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open 2012;2:e001663. https://doi.org/10.1136/bmjopen-2012-001663.

[20]    Bhan I, Camargo CA, Wenger J, Ricciardi C, Ye J, Borregaard N, et al. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol 2011;127:1302-1304.e1. https://doi.org/10.1016/j.jaci.2010.12.1097.

[21]    Lansiaux É, Pébaÿ PP, Picard J-L, Forget J. Covid-19 and vit-d: Disease mortality negatively correlates with sunlight exposure. Spat Spatio-Temporal Epidemiol 2020;35:100362. https://doi.org/10.1016/j.sste.2020.100362.

[22]    Whittemore PB. COVID-19 fatalities, latitude, sunlight, and vitamin D. Am J Infect Control 2020;48:1042–4. https://doi.org/10.1016/j.ajic.2020.06.193.


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November 27, 2020 at 09:02AM