Upregulating Human Cathelicidin Antimicrobial Peptide LL-37 Expression May Prevent Severe COVID-19 Inflammatory Responses and Reduce Microthrombosis

Abstract

COVID-19 is characterized by hyperactivation by inflammatory cytokines and recruitment of macrophages, neutrophils, and other immune cells, all hallmarks of a strong inflammatory response that can lead to severe complications and multi-organ damage. Mortality in COVID-19 patients is associated with a high prevalence of neutrophil extracellular trap (NET) formation and microthrombosis that are exacerbated by hyperglycemia, diabetes, and old age. SARS-CoV-2 infection in humans and non-human primates have revealed long-term neurological consequences of COVID-19, possibly concomitant with the formation of Lewy bodies in the brain and invasion of the nervous system via the olfactory bulb. In this paper, we review the relevance of the human cathelicidin LL-37 in SARS-CoV-2 infections. LL-37 is an immunomodulatory, host defense peptide with direct anti-SARS-CoV-2 activity, and pleiotropic effects on the inflammatory response, neovascularization, Lewy body formation, and pancreatic islet cell function. The bioactive form of vitamin D and a number of other compounds induce LL-37 expression and one might predict its upregulation, could reduce the prevalence of severe COVID-19. We hypothesize upregulation of LL-37 will act therapeutically, facilitating efficient NET clearance by macrophages, speeding endothelial repair after inflammatory tissue damage, preventing α-synuclein aggregation, and supporting blood-glucose level stabilization by facilitating insulin release and islet β-cell neogenesis. In addition, it has been postulated that LL-37 can directly bind the S1 domain of SARS-CoV-2, mask angiotensin converting enzyme 2 (ACE2) receptors, and limit SARS-CoV-2 infection. Purposeful upregulation of LL-37 could also serve as a preventative and therapeutic strategy for SARS-CoV-2 infections.

Keywords: COVID-19; LL-37; NET clearance; SARS-CoV-2; alpha synuclein; cathelicidin; diabetes; neutrophil extracellular trap (NET).

Figure 1

(A) The structure of (13)C,(15)N-labeled LL-37 determined by three-dimensional triple-resonance NMR spectroscopy for LL-37 in complex with micelles. (9) LL-37’s alpha-helical secondary structure is evident. (B) The 37 amino acid sequence of LL-37. At physiological pH LL-37 has a resulting net charge of +6.

Figure 2

Graphical summary of interactions between SARS-CoV-2 and lung epithelium, instigating NET production and the disruption or antagonistic behavior of LL-37 for these interactions. Adapted from “The Propagation of Immunothrombosis by Leukocytes and Platelets”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.

Figure 3

Interaction scheme of LL-37, NETosis, hyperglycemia, and diabetes that lead to severe COVID-19 symptoms. Relevant interactions are cited below. Created with BioRender.com.

Figure 4

Interaction scheme of SARS-CoV-2 and the brain overlaid with potential antagonistic or therapeutic benefits of LL-37. Adapted from “Brain Vascular System” and “Progression of Parkinson’s Disease by the Substantia Niagra”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.