Keywords: vitamin D, innate immunity, respiratory infections, COVID-19, SARS-CoV-2, sunlight
Acute respiratory viral infections, including COVID-19, have a strong correlation with vitamin D deficiency. They are also highly seasonal and peak in winter when the availability of the UVB component of sunlight is low. UVB is known to induce the production of vitamin D in the skin. However, vitamin D supplementation has little or no effect on preventing respiratory infections in adults. Thus, UVB light offers the immune system significant advantages that are not produced by oral vitamin D supplements.
This paper assumes that UVB light stimulates the production of cathelicidin and other antimicrobial peptides (AMPs) in the skin. These AMPs are carried by the blood into the airways and improve the innate immunity of the airways. AMPs are also known as "natural antibiotics" because they protect not only against microbes, but also against enveloped viruses, including influenza and coronaviruses.
The skin and respiratory tract surfaces play a similar role in the body – they act as a barrier between the body and the outside world. Many of the same AMPs, including cathelicidin, are produced and act in the skin, the surface of the airways, 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 at safe levels, depending on the skin phototype (dark skin may need 5-6 times more exposure than light skin), is necessary to maintain normal innate immunity . Vitamin D supplements cannot replace UVB exposure.
Seasonality of the infection
Currently (end of November 2020) the increase in COVID-19 infections in the northern hemisphere is in line with seasonal expectations. COVID-19 is no exception in respiratory infections. Its seasonality has been observed in both hemispheres. The inverse correlation between UV sunlight and SARS-COV-2 positivity (1) has been reported. The rise in COVID cases comes a little before the regular flu season. A significant portion of the population has been exposed to less than usual sunlight in recent months due to the precautions taken for COVID-19.
The seasonal nature of influenza has long been known (2). This seasonality is associated with low exposure to the UVB component (wavelengths 280-320 nm) in sunlight, which leads to inadequate vitamin D levels. Among other things, vitamin D is required for AMP production, so that respiratory infections increase. Winter was associated with a seasonal impairment in AMP production (3). In the US, respiratory infections are booming in winter and almost completely disappearing in summer, and the death rate in winter is 25% higher than in summer (4). Many observational studies have shown that moderate UVB exposure resulted in a sharp decrease in respiratory infections (5). (6) reports a weekly inverse correlation between sunlight and the spread of the zoonotic influenza virus H1N1 2009 (“swine flu”).
The lack of UVB exposure and low vitamin D levels are strongly linked and with a susceptibility to respiratory infections. The hypothesis that UVB exposure can be replaced with vitamin D supplementation to help maintain innate respiratory immunity has somehow become entrenched. This flawed assumption persists despite several studies in which oral supplementation with vitamin D has shown little or no benefit for respiratory immunity (7).
Although it is well known in mid-latitudes in Europe that moderate solar radiation is beneficial (8), such studies have not been funded (9).
Vitamin D3 is produced by the skin when it is exposed to UVB light. It can also be taken with food. In either case, it is inactive until it is metabolized to 25 (OH) D (25-hydroxy-vitamin D) in the liver. 25 (OH) D then metabolizes further to 1,25 (OH) 2D3 (1,25-dihydroxyvitamin D3) in the kidneys, as well as in many other organs, including the skin and epithelial cells of the respiratory tract.
Innate Immune System & AMPs
The innate immune system of humans reacts to pathogens without them having to be recognized. This is in contrast to the adaptive immune system, which has to recognize the respective pathogen before it counteracts it with antigens or T cells.
This makes AMPs crucial for the defense against novel respiratory viruses such as SARS-CoV-2, which are not recognized by the body. Cathelicidine and other AMPs are the tools of the innate immune response. Cathelicidins break down viral and microbial membranes and also alert the rest of the immune system to act (10), (11). LL-37 (with the precursor protein hCAP18) is the only known human cathelicidin. Cathelicidin acts as a chemical protective shield in the skin. Cathelicidins are made from keratinocytes (17) in many tissues of the skin up 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).
For a long time it was observed how rarely sunburns (severely damaging skin and suppression of the adaptive immune system) lead to opportunistic infections.
When the skin is damaged, AMPs are produced. Their main role is to provide local antimicrobial protection to damaged skin, but they also migrate in the blood (13) and can protect the airways. LL-37 has been shown to directly inhibit influenza virus in humans (14).
In 2005 Mallibris et al. conducted a study in which they exposed the buttocks of eight volunteers to UVB (15). The study summarized the results under the title "UVB upregulates the hCAP18 mRNA of the antimicrobial protein in human skin". The single exposure of a single buttock to the minimal erythema dose of UVB led to a 2.3-fold increase in the hCAP18 level in the exposed skin within 24 hours. This amount of UVB cannot significantly increase the body's vitamin D levels. Therefore, the production of additional hCAP18 was solely due to the UVB stimulation, not to increased vitamin D levels.
Zasloff (16) carefully concluded that sunlight "activates an arm of innate immunity in the skin". In addition to the production of hCPA18 / LL-37, Zasloff suggested several other mechanisms.
Other experiments (17) with UVB successfully induced defensins and other universal AMPs in keratinocytes. This led to the conclusion that UVB exposure increases local production of AMPs and strengthens innate immunity (18).
In hindsight, it's not surprising that the skin reacts to ultraviolet radiation in much the same way that it reacts to other stimuli such as physical injury or infection.
UVB light can increase the production of AMPs in the skin through an increased local production of 1,25-dihydroxyvitamin D from 25 (OH) D. Cathelicidin and other AMPs produced in the skin migrate in the blood to other parts of the body, including the epithelial surfaces of the respiratory tract, thereby strengthening innate respiratory immunity. It is also possible that UVB activates blood cells that can pass through the exposed skin and produce AMPs (neutrophils, macrophages, lymphocytes, etc.), and they produce AMPs in other tissues as well.
Vitamin D supplementation does not noticeably increase blood LL-37 levels (19), (20) even if it does significantly increase 25 (OH) D levels.
(20) reported that a subgroup of the test subjects showed an increase in LL-37 concentrations of ~ 20%, which corresponds to a 200% increase in 25 (OH) D concentrations in the blood after ergocalciferol supplementation. This relationship is insignificant and could be explained by their initial lack of 25 (OH) D and / or exposure to sunlight, which researchers are not aware of
(19) showed a decrease in disease with supplementation. The supplement was Vigantol – vitamin D3 dissolved in triglyceride. Several studies from the 1930s showed a significant improvement in respiratory immunity from ingesting cod liver oil (5), which contained not only vitamin D but also omega-3 fatty acids and vitamin A. The effects of a combined vitamin D / omega-3 supplement is a promising avenue for research. A word of caution: some sources say that modern techniques of cod liver oil and other fish oil preparations remove most of the vitamin D.
(21) and (22) reported an inverse correlation between sunlight UV and COVID-19 mortality. This could be due to the anti-inflammatory effects of vitamin D and is beyond the scope of this document.
Exposure to UVB in sunlight or artificial UVB sources in appropriate amounts and adjusted by skin phototype (dark skin may need 5-6 times more exposure than light skin) is required to maintain normal innate immunity. Vitamin D supplements don't offer the same benefits or immunity as UVB exposure. UVB stimulates the production of cathelicidin and other AMPs in the skin and / or certain blood cells that travel through the skin. These AMPs are carried by the blood to the surfaces of the airways and improve innate airway immunity.
No competing interests
The author does not declare a competing interest.
No funding was provided for this work.
Many thanks to AO for contributing to this paper.
Comment from an author
- I bent over backwards not to say the ozone fraud was behind suppressing research on the health benefits of UVB. Even so, this article was rejected by preprints.org.
- People who wear masks outside further decrease the amount of beneficial UVB.
- Innate immunity is surprisingly rarely mentioned in the discussions of the response to COVID-19, but it protects most people from disease when exposed to SARS-COV-2.
(1) Tang L, Liu M, Ren B, Wu Z, Yu X, Peng C, et al. The UV radiation dose of sunlight correlates negatively with the percentage positive of SARS-CoV-2 and four other common human coronaviruses in the US 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 in US Mortality Rates: Role of Solar Ultraviolet B Doses, Vitamin D, Gene Expression, 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 from 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 for the Prevention of Acute Respiratory 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 and Negative Effects of Sun Exposure: Can all of the potential benefits be obtained from 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 Controlling Skin 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 antimicrobial cathelicidin peptide LL-37 is involved in the re-epithelialization of human skin wounds and has no 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 on 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 innate host defense in 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 by a mechanism that differs from that of the surfactant protein D or the 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 hCAP18 mRNA of the antimicrobial protein 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 defense of human skin. J Invest Dermatol 2005; 125: xvi – xvii. https://doi.org/10.1111/j.0022-202X.2005.23924.x.
(17) Glasses R., Navid F., Schuller W., Jantschitsch C., Harder J., Schröder J. M., 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 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 infections: a randomized, 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: 1302-1 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 correlates negatively with solar radiation. Spat Spatio-Temporal Epidemiol 2020; 35: 100362. https://doi.org/10.1016/j.sste.2020.100362.
(22) Whittemore PB. COVID-19 Deaths, Latitude, Sunlight, and Vitamin D. Am J Infect Control 2020; 48: 1042-4. https://doi.org/10.1016/j.ajic.2020.06.193.