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.

Keywords: African American; COVID-19; Vitamin D deficiency; air pollution; carbon nanoparticles; cathelicidin/LL37; citrullination of peptide; tobacco smoke.

Figure 1

LL37 Inactivation of envelope viruses is stimulated by Vitamin D and blocked by air pollution. Humans obtain Vitamin D from sunlight, and from supplements and food. The active form of Vitamin D, 1,25(OH)₂D binds to the Vitamin D receptor, which stimulates transcription of Cathelicidin. Cathelicidin is cleaved to generate the cationic antimicrobial peptide LL37. LL37 binds to and disables envelope viruses. Air pollution inactivates LL37 by removing the charge, leaving viruses to replicate unimpeded.