Vitamin D Deficiency and Air Pollution Exacerbate COVID-19 Through Suppression of Antiviral Peptide LL37

Abstract

Vitamin D deficiency and insufficiency (VDD) are widely recognized as risk factors for respiratory tract infections. Vitamin D influences expression of many genes with well-established relevance to airway infections and relevant to immune system function. Recently, VDD has been shown to be a risk factor for acquisition and severity of COVID-19. Thus, treating VDD presents a safe and inexpensive opportunity for modulating the severity of the disease. VDD is common in those over 60 years of age, many with co-morbid conditions and in people with skin pigmentation sufficient to reduce synthesis of vitamin D. Exposure to fine particulate air pollution is also associated with worse outcomes from COVID19. Vitamin D stimulates transcription of cathelicidin which is cleaved to generate LL37. LL37 is an innate antimicrobial with demonstrated activity against a wide range of microbes including envelope viruses. LL37 also modulates cytokine signaling at the site of infections. Fine particles in air pollution can interfere with LL37 destruction of viruses and may reduce effective immune signaling modulation by LL37. While vitamin D influences transcription of many immune related genes, the weakened antimicrobial response of those with VDD against SARS-CoV-2 may be in part due to reduced LL37. Conclusion: Vitamin D plays an important role reducing the impact of viral lung disease processes. VDD is an acknowledged public health threat that warrants population-wide action to reduce COVID-19 morbidity and mortality. While vitamin D influences transcription of many immune related genes, the weakened antimicrobial response of those with VDD against SARS-CoV-2 may be in part due to reduced LL37. Action is needed to address COVID-19 associated risks of air pollution from industry, transportation, domestic sources and from primary and second hand tobacco smoke.

A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency

“…In the lungs, formation of the peptide LL37, an innate immune system component that, among other things, attacks enveloped viruses such as SARS-CoV-2 and modulates the immune system, requires sufficient vitamin D levels ( 28 , 32 , 117 , 155 ). LL37 is inhibited by carbon and other nanoparticles in air pollution ( 32 ).…”

“…In the lungs, formation of the peptide LL37, an innate immune system component that, among other things, attacks enveloped viruses such as SARS-CoV-2 and modulates the immune system, requires sufficient vitamin D levels ( 28 , 32 , 117 , 155 ). LL37 is inhibited by carbon and other nanoparticles in air pollution ( 32 ). Therefore, vitamin D deficient individuals can be expected to be at increased risk of both developing COVID-19 and experiencing the “cytokine storm” if they become infected, particularly in areas of the world with high levels of air pollution ( 32 , 117 ).…”

“…LL37 is inhibited by carbon and other nanoparticles in air pollution (32). Therefore, vitamin D deficient individuals can be expected to be at increased risk of both developing COVID-19 and experiencing the "cytokine storm" if they become infected, particularly in areas of the world with high levels of air pollution (32,117).…”

SARS‐CoV‐2 infection, COVID‐19 pathogenesis, and exposure to air pollution: What is the connection?

“…[166][167][168] Furthermore, fine particles in air pollutants have been suggested to alter the charge and, subsequently, the activity of LL37 by promoting citrullination of the AMP. 169 As previously mentioned, AMPs may be involved in regulating SARS-CoV-2 infection by disrupting the viral envelope. In addition, AMPs also function in regulating immune responses by stimulating TLR activation, cytokine production, immune cell chemotaxis, and neutrophil and mast cell degranulation.…”

Environment and COVID-19: Pollutants, impacts, dissemination, management and recommendations for facing future epidemic threats

“…In addition, fine particulate matter contains organic pollutants, heavy metals, dust, and pollen that can disrupt immune responses ( Tsatsakis et al, 2020 ). Particulate matter can interfere with LL37 (a peptide involved in innate immune response) and may reduce effective immunity of the organism ( Crane-Godreau et al, 2020 ). Some research has correlated fine particulate matter (PM2.5, PM10) with confirmed cases of deaths due to COVID-19 ( Table 1 ).…”