LL-37 Peptide: Bacteria Research

LL-37, considered to be an antimicrobial peptide and member of the cathelicidin family, matches the first amphipathic alpha-helical peptide sequence. They are tiny, cationic peptides. In particular, neutrophil granules retain them as dormant precursors, and neutrophil elastase appears to cleave them when needed.

Studies suggest the gastrointestinal tract, epididymis, lungs, epithelial cells of the skin, circulating neutrophils, myeloid bone marrow cells, and other cells and organs may express LL-37. Squamous epithelium of the esophagus, mouth, and tongue, as well as the mucosal lining of the colon and bronchi, have also been suggested to express the gene.

In addition, research suggests that skin-absorbed vitamin D may promote macrophage LL-37 synthesis. Investigations purport that in inflamed or wounded areas, LL-37 may be a crucial first line of defense against infection and the systemic invasion of microbes. Aside from being purportedly highly resistant to proteolytic breakdown in solution, it may be cytotoxic to normal eukaryotic cells and bacteria. Many different types of bacteria, viruses with capsids, and fungi are hypothesized to be susceptible to their antimicrobial effects. In addition to their direct antimicrobial potential, they are speculated to be crucial in inducing some host defensive responses.

LL-37 Peptide: Mechanism of Action

Many researchers suppose that LL-37 disrupts the bacterial membrane in its direct antibacterial effect. Findings imply that, in general, there are three ways that AMPs that disrupt membranes are thought to work: (i) creating a hydrophilic pore across the membrane with a tightly coiled bundle of amphiphilic peptides (the barrel-stave conformation); (ii) transforming the membrane into a lipid headgroup lined pore (the toroidal conformation); or (iii) staying on the surface of the membrane (the carpet mode) until the threshold is reached, which allows the breakdown of membrane integrity. Nevertheless, LL-37's action mechanism appears to defy classification; studies suggest it does not penetrate the membrane and yet may maintain a surface-to-surface orientation independent of peptide content, membrane charge, ion presence, or temperature.

In addition, research suggests that, unlike other α-helical, amphipathic AMPs, LL-37 may not prefer charged membranes. Its minimum inhibitory concentration (MIC) is believed to vary between 1 and 10 μM for different Gram-positive and Gram-negative bacteria types. However, concentrations ranging from 13 to 25 μM may cause cytotoxicity in animals. Therefore, despite its lack of specificity, the carpet mechanism was postulated as the method by which LL-37 kills cells.

Nonetheless, fluorescence studies and other data pointed to a pore-forming process, and LL-37 was suggested to damage the lipid bilayer without rupturing the membrane into tiny pieces. Also unclear is how LL-37 may act on mammalian cell membranes; one theory is that it may hinder the ability of certain bacteria to invade epithelial cell membranes by reducing their fluidity and, by extension, their permeability. Because of this, the exact mechanism of action of LL-37 is still mostly unknown, and research into it has taken a back seat to efforts to create more potent LL-37 variants by systematic mutation.

A hypothesized indirect function of LL-37 is to modulate the immunological response to pathogens. It has been theorized to have dual functionality in research models because it may activate different types of immune cells. Neutrophils and kallikrein include proteinase 3, which cleaves hCAP18 when it is stimulated by proinflammatory signals and discharged into the extracellular environment. Specialists speculate that inflammasome activation and type 1 interferon production are two inflammatory responses that may be stimulated by LL-37 exposure, the recruitment of inflammatory cells, and the generation of M1 macrophages. It has been asserted that strong anti-inflammatory potential of LL-37 might include blocking pathogenic bacterial invasion and inflammatory reactions, downregulating inflammatory cytokine responses, and neutralizing LPS-induced TLR4 activation.

LL-37 Peptide and Immunity

The immunological activity of LL-37 against several bacterial species has been studied extensively, and the results suggest that it may be helpful in the context of many infections. Chronic infections, often caused by staphylococcus epidermidis, may be common in research models with indwelling devices and often do not respond to antibiotic procedures. Researchers indicated that LL-37 may positively impact staph epidermidis. In particular, according to the research, LL37 seemed to have inhibited biofilm formation and considerably reduced bacterial surface attachment. Because of this, it appears to have promising implications in the context of infection research exploring bacteria development after the installation of medical devices.

Scientists fear that bacteria are becoming more resistant to traditional antibiotics. Therefore, researchers have been studying the potential of LL-37 and other substances to determine how well they may eliminate intracellular and extracellular infections. Recent research has ascertained that LL-37 might be more successful than traditional antibiotics at killing intracellular and extracellular staph aureus. This is speculated due to its alleged greater potency, quicker killing rate, and quantitative efficacy.

LL-37 Peptide, Infections and Viruses

In addition to its possible antibacterial properties, research suggests that LL-37 may influence viruses and fungi. In particular, it has been suggested to be a potentially effective component of the immune response to the influenza A virus. A recent research study examined the potential of viral membranes using electron microscopy. In contrast to collectins and defensins, LL-37 seems to damage viral membranes rather than stimulate viral aggregation. This ascertains its anti-influenza A function is distinct from surfactant proteins D and defensins. LL-37 has also exhibited significant antifungal activities within laboratory conditions.

Due to the constant presence of heat and moisture within physiological systems, Candida albicans—one of the most prevalent fungal pathogens—may be challenging to cure. Multiple investigations have indicated that LL-37 might be effective against the yeast Candida albicans. The results implied that LL-37 may have had multiple effects on different types of fungi. The cell wall's integrity and layout may be altered, and it has been hypothesized to regulate the expression of genes that play several roles in fungal growth and reproduction.

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References:

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[ii] Neville; et al. Lipid Headgroup Discrimination by Antimicrobial Peptide LL-37: Insight in Mechanism of Action.

[iii] Wildman; et al. Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37. Biochemistry 2003, 42, 6545-6558.

[iv] Tanaka; et al. Sensitivity of Actinobacillus actinomyecetemcomitans and Capnocytophaaga spp. To the bactericidal action of LL-37: a cathelicidin found in human leukocytes and epithelium. Oral Microbiol Immunol. 200 Aug;15(4):226-31.

[v] Henzler-Wildman KA; et al. Perturbation of the hydrophobic core of lipid bilayers by the human antimicrobial peptide LL-37. Biochemistry. 2004 Jul 6;43(26):8459-69.

[vi] Barns; Weisshaar. Real-time Attack of LL-37 on Single Bacillus subtilis Cells. Biochim Biophys Acta. 2013

[vii] Hell; et al. Human cathelicidin peptide LL37 inhibits both attachment capability and biofilm formation of Staphylococcus epidermidis. Lett Appl Microbiol. 2010 Feb;50(2):211-5. 2009 Nov 23.

[viii] Noore j. Cationic antimicrobial peptide LL-37 is effective against both extra- and intracellular staphylococcus aureus.

[ix] Tripathi, S; et al. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D of defensins. Journal of General Virology (2013), 94, 40-49.

[x] Tsai PW; et al. Responses of Candida albicans to the human antimicrobial peptide LL-37. J Microbiol. 2014 Jul:52(7):581-9.2014.