The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics

Sancho‐Vaello, Enea; Gil, David; François, Patrice; Bonetti, Eve-Julie; Kreir, Mohamed; Pothula, Karunakar R.; Kleinekathöfer, Ulrich; Zeth, Kornelius

doi:10.1038/s41598-020-74401-5

Cited by 85 publications

(62 citation statements)

References 105 publications

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“…The "barrel stave" mechanism is based on the raising of structures that resemble the aligned wooden staves of a barrel, which include the hydrophilic inner surface of the "staves". Another process is called "connecting channels", by which proteins combine with the cell membrane and open pores into the cell [26][27][28]. Our in silico analysis was consistent with the net charge and secondary structure of each peptide, since those with lower net charge and/or lower helicity showed a lesser extent of interaction with simulated membranes, as revealed by the lower number of membrane-embedded residues.…”

Section: Discussionsupporting

confidence: 78%

Bioinformatic Analysis of Genome-Predicted Bat Cathelicidins

et al. 2021

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Bats are unique in their potential to serve as reservoir hosts for intracellular pathogens. Recently, the impact of COVID-19 has relegated bats from biomedical darkness to the frontline of public health as bats are the natural reservoir of many viruses, including SARS-Cov-2. Many bat genomes have been sequenced recently, and sequences coding for antimicrobial peptides are available in the public databases. Here we provide a structural analysis of genome-predicted bat cathelicidins as components of their innate immunity. A total of 32 unique protein sequences were retrieved from the NCBI database. Interestingly, some bat species contained more than one cathelicidin. We examined the conserved cysteines within the cathelin-like domain and the peptide portion of each sequence and revealed phylogenetic relationships and structural dissimilarities. The antibacterial, antifungal, and antiviral activity of peptides was examined using bioinformatic tools. The peptides were modeled and subjected to docking analysis with the region binding domain (RBD) region of the SARS-CoV-2 Spike protein. The appearance of multiple forms of cathelicidins verifies the complex microbial challenges encountered by these species. Learning more about antiviral defenses of bats and how they drive virus evolution will help scientists to investigate the function of antimicrobial peptides in these species.

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Section: Discussionsupporting

confidence: 78%

Bioinformatic Analysis of Genome-Predicted Bat Cathelicidins

et al. 2021

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“…Nevertheless, this control of processing and externalization could occur in vivo both inside the cells (to release adequate amounts of the antimicrobial peptide in case of infection by bacteria, virus, and fungi) and/or outside the cells (if LL-37 concentration is too high in the bloodstream). This regulation is crucial because the LL-37 killing mechanisms are not specific so that in excess it can become a cytotoxic agent towards commensal bacteria and/or host cells [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxyvitamin D potentializes extracellular cathelicidin release from human PBMC stimulated ex vivo with either bacterial (LPS) or viral (P: IC) mimetics

et al. 2022

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Human cathelicidin refers to the cationic antimicrobial peptide hCAP18/LL-37. LL-37 is formed by cleavage of the propeptide hCAP18 coded with CAMP gene. The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)D), has been shown to induce the CAMP gene expression through promoter activation. We previously failed to demonstrate in a clinical trial that supplementation of 25-hydroxyvitamin D (25(OH)D) improves LL-37 serum levels. The aim of this work was to evaluate the impact of 25(OH)D supplementation on intracellular expression of CAMP and secretion of LL-37 in an ex vivo model using the peripheral blood mononuclear cells (PBMC). PBMC collected from healthy donors and incubated with different concentrations of 25(OH)D (0 ng/ml: control (D0); 25 ng/ml: deficient (D25); 75 ng/ml: physiological (D75); 125 ng/ml: supraphysiological (D125)) were stimulated or not with lipopolysaccharide (LPS, 100 ng/ml) or synthetic double-stranded RNA Poly (I: C) (PIC, 10 µg/ml). The intracellular expressions of the CAMP gene and the hCAP18 peptide were measured respectively after 24-h and 48-h incubation periods. The concentration of LL-37 was determined in the culture medium after 48-h incubation. 25(OH)D significantly induced CAMP gene expression at 24 h with a maximum effect at a dose of D125 in either unstimulated (tenfold expression) or stimulated (LPS: 100-fold expression; PIC: 15-fold expression) conditions. Intracellular hCAP18 peptide was overexpressed at 48 h under unstimulated (1.5-fold, D125) and stimulated conditions, LPS (twofold, D125) and PIC (2.5-fold, D125). The secretion of LL-37 in the culture medium was significantly induced by 25(OH)D only in both stimulated (LPS and PIC) conditions in a dose-dependent manner. Our results demonstrate that 25(OH)D incubation increases intracellular expression of CAMP and hCAP18, but extracellular secretion of LL-37 antimicrobial peptide is increased by 25(OH)D only when PBMC from healthy donors were stimulated with bacterial or viral immune mimetic.

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“…This oxidase is the one that converts 25(OH)-VD into the active form 1,25(OH)-VD, which, in autocrine mode, stimulates the antimicrobial activity of macrophages through the VDR/RXR signaling pathway, inducing the endogenous production of cathelicidin hCAP-18 and its derivative antimicrobial peptide LL-37. LL37 is able to interact with the molecules of the bacterial wall and perforate the cytoplasmic membrane, resulting in the death of the bacterial cell [ 66 , 67 , 68 , 69 ].…”

Section: Resultsmentioning

confidence: 99%

Potential Role of Vitamins A, B, C, D and E in TB Treatment and Prevention: A Narrative Review

et al. 2021

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(1) Background: Tuberculosis (TB) is one of the world’s top infectious killers, in fact every year 10 million people fall ill with TB and 1.5 million people die from TB. Vitamins have an important role in vital functions, due to their anti-oxidant, pro-oxidant, anti-inflammatory effects and to metabolic functions. The aim of this review is to discuss and summarize the evidence and still open questions regarding vitamin supplementation as a prophylactic measure in those who are at high risk of Mycobacterium tuberculosis (MTB) infection and active TB; (2) Methods: We conducted a search on PubMed, Scopus, Google Scholar, EMBASE, Cochrane Library and WHO websites starting from March 1950 to September 2021, in order to identify articles discussing the role of Vitamins A, B, C, D and E and Tuberculosis; (3) Results: Supplementation with multiple micronutrients (including zinc) rather than vitamin A alone may be more beneficial in TB. The WHO recommend Pyridoxine (vitamin B6) when high-dose isoniazid is administered. High concentrations of vitamin C sterilize drug-susceptible, MDR and extensively drug-resistant MTB cultures and prevent the emergence of drug persisters; Vitamin D suppresses the replication of mycobacterium in vitro while VE showed a promising role in TB management as a result of its connection with oxidative balance; (4) Conclusions: Our review suggests and encourages the use of vitamins in TB patients. In fact, their use may improve outcomes by helping both nutritionally and by interacting directly and/or indirectly with MTB. Several and more comprehensive trials are needed to reinforce these suggestions.

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The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics

Cited by 85 publications

References 105 publications

Bioinformatic Analysis of Genome-Predicted Bat Cathelicidins

Bioinformatic Analysis of Genome-Predicted Bat Cathelicidins

25-Hydroxyvitamin D potentializes extracellular cathelicidin release from human PBMC stimulated ex vivo with either bacterial (LPS) or viral (P: IC) mimetics

Potential Role of Vitamins A, B, C, D and E in TB Treatment and Prevention: A Narrative Review

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