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1
Nagant, C., B. Pitts, K. Nazmi, M. Vandenbranden, J. G. Bolscher, P. S. Stewart, and J. P. Dehaye. "Identification of Peptides Derived from the Human Antimicrobial Peptide LL-37 Active against Biofilms Formed by Pseudomonas aeruginosa Using a Library of Truncated Fragments." Antimicrobial Agents and Chemotherapy 56, no. 11 (August 20, 2012): 5698–708. http://dx.doi.org/10.1128/aac.00918-12.
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ABSTRACTPersistentPseudomonas aeruginosainfections are a major cause of morbidity and mortality in cystic fibrosis (CF) patients and are linked to the formation of a biofilm. The development of new biofilm inhibition strategies is thus a major challenge. LL-37 is the only human antimicrobial peptide derived from cathelicidin. The effects on theP. aeruginosaPAO1 strain of synthetic truncated fragments of this peptide were compared with the effects of the original peptide. Fragments of LL-37 composed of 19 residues (LL-19, LL13-31, and LL7-25) inhibited biofilm formation. The strongest antibiofilm activity was observed with the peptides LL7-37 and LL-31, which decreased the percentage of biomass formation at a very low concentration. Some peptides were also active on the bacteria within an established biofilm. LL7-31, LL-31, and LL7-37 increased the uptake of propidium iodide (PI) by sessile bacteria. The peptide LL7-37 decreased the height of the biofilm and partly disrupted it. The peptides active within the biofilm had an infrared spectrum compatible with an α-helix. LL-37, but not the peptides LL7-31 and LL7-37, showed cellular toxicity by permeabilizing the eukaryotic plasma membrane (uptake of ethidium bromide and release of lactate dehydrogenase [LDH]). None of the tested peptides affected mitochondrial activity in eukaryotic cells. In conclusion, a 25-amino-acid peptide (LL7-31) displayed both strong antimicrobial and antibiofilm activities. The peptide was even active on cells within a preformed biofilm and had reduced toxicity toward eukaryotic cells. Our results also suggest the contribution of secondary structures (α-helix) to the activity of the peptides on biofilms.
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Sieprawska-Lupa, Magdalena, Piotr Mydel, Katarzyna Krawczyk, Kinga Wójcik, Magdalena Puklo, Boguslaw Lupa, Piotr Suder, et al. "Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus-Derived Proteinases." Antimicrobial Agents and Chemotherapy 48, no. 12 (December 2004): 4673–79. http://dx.doi.org/10.1128/aac.48.12.4673-4679.2004.
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ABSTRACT Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus, a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.
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Perez-Perez, David A., Teresa de J. Villanueva-Ramirez, Adriana E. Hernandez-Pedraza, Nestor G. Casillas-Vega, Patricia Gonzalez-Barranco, and Xristo Zarate. "The Small Metal-Binding Protein SmbP Simplifies the Recombinant Expression and Purification of the Antimicrobial Peptide LL-37." Antibiotics 10, no. 10 (October 19, 2021): 1271. http://dx.doi.org/10.3390/antibiotics10101271.
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(1) Background: The cathelicidin peptide LL-37 is a prominent molecule with many biological activities, including antimicrobial. Due to its importance, here, we describe the production of LL-37 tagged with SmbP, a relatively new carrier protein that improves the production of recombinant proteins and peptides in Escherichia coli. We present an alternative method for the rapid expression, purification, and antimicrobial evaluation of LL-37, that involves only one purification step. (2) Methods: A DNA construct of SmbP_LL-37 was transformed into E. coli BL21(DE3); after overnight expression, the protein was purified directly from the cell lysate using immobilized metal-affinity chromatography. SmbP_LL-37 was treated with Enterokinase to obtain the free LL-37 peptide. The antimicrobial activity of both SmbP_LL-37 and free LL-37 was determined using the colony forming unit assay method. (3) Results: SmbP_LL-37 was observed in the soluble fraction of the cell lysate; after purification with IMAC, protein gel electrophoresis, and analysis by ImageJ, it showed 90% purity. A total of 3.6 mg of SmbP_LL-37 was produced from one liter of cell culture. SmbP_LL-37 and free LL-37 both showed inhibition activity against Staphylococcus aureus and Escherichia coli. (4) Conclusions: The SmbP fusion protein is a valuable tool for producing biologically-active LL-37 peptide. The production method described here should be of interest for the expression and purification of additional cationic peptides, since it cuts the purification time considerably prior to determination of antimicrobial activity.
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Sigurdardottir, Thorgerdur, Pia Andersson, Mina Davoudi, Martin Malmsten, Artur Schmidtchen, and Mikael Bodelsson. "In Silico Identification and Biological Evaluation of Antimicrobial Peptides Based on Human Cathelicidin LL-37." Antimicrobial Agents and Chemotherapy 50, no. 9 (September 2006): 2983–89. http://dx.doi.org/10.1128/aac.01583-05.
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ABSTRACT Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.
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Yang, De, Qian Chen, Albert P. Schmidt, G. Mark Anderson, Ji Ming Wang, Joseph Wooters, Joost J. Oppenheim, and Oleg Chertov. "Ll-37, the Neutrophil Granule–And Epithelial Cell–Derived Cathelicidin, Utilizes Formyl Peptide Receptor–Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells." Journal of Experimental Medicine 192, no. 7 (October 2, 2000): 1069–74. http://dx.doi.org/10.1084/jem.192.7.1069.
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We have previously shown that antimicrobial peptides like defensins have the capacity to mobilize leukocytes in host defense. LL-37 is the cleaved antimicrobial 37-residue, COOH-terminal peptide of hCAP18 (human cationic antimicrobial protein with a molecular size of 18 kD), the only identified member in humans of a family of proteins called cathelicidins. LL-37/hCAP18 is produced by neutrophils and various epithelial cells. Here we report that LL-37 is chemotactic for, and can induce Ca2+ mobilization in, human monocytes and formyl peptide receptor–like 1 (FPRL1)-transfected human embryonic kidney 293 cells. LL-37–induced Ca2+ mobilization in monocytes can also be cross-desensitized by an FPRL1-specific agonist. Furthermore, LL-37 is also chemotactic for human neutrophils and T lymphocytes that are known to express FPRL1. Our results suggest that, in addition to its microbicidal activity, LL-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and T cells to sites of microbial invasion by interacting with FPRL1.
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Rinker, Sherri D., Michael P. Trombley, Xiaoping Gu, Kate R. Fortney, and Margaret E. Bauer. "Deletion ofmtrCin Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon." Infection and Immunity 79, no. 6 (March 28, 2011): 2324–34. http://dx.doi.org/10.1128/iai.01316-10.
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ABSTRACTHaemophilus ducreyiresists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, α-defensins, and β-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance inH. ducreyi. We found a proton motive force-dependent effect onH. ducreyi's resistance to LL-37 and β-defensin HBD-3, but not α-defensin HNP-2. Deletion of the membrane fusion protein MtrC renderedH. ducreyimore sensitive to LL-37 and human β-defensins but had relatively little effect on α-defensin resistance. ThemtrCmutant 35000HPmtrCexhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type bytrans-complementation withmtrC. Similar phenotypes were reported in acpxAmutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HPmtrC. AcpxRmutant had wild-type levels of antimicrobial peptide resistance; acpxAmutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HPmtrCwas more sensitive than thecpxAmutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HPmtrChad lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive force-dependent resistance to LL-37 and human β-defensins. This is the first report of a β-defensin resistance mechanism inH. ducreyiand shows that LL-37 resistance inH. ducreyiis multifactorial.
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Zhang, Yingxia, Jayaram Lakshmaiah Narayana, Qianhui Wu, Xiangli Dang, and Guangshun Wang. "Structure and Activity of a Selective Antibiofilm Peptide SK-24 Derived from the NMR Structure of Human Cathelicidin LL-37." Pharmaceuticals 14, no. 12 (November 30, 2021): 1245. http://dx.doi.org/10.3390/ph14121245.
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The deployment of the innate immune system in humans is essential to protect us from infection. Human cathelicidin LL-37 is a linear host defense peptide with both antimicrobial and immune modulatory properties. Despite years of studies of numerous peptides, SK-24, corresponding to the long hydrophobic domain (residues 9–32) in the anionic lipid-bound NMR structure of LL-37, has not been investigated. This study reports the structure and activity of SK-24. Interestingly, SK-24 is entirely helical (~100%) in phosphate buffer (PBS), more than LL-37 (84%), GI-20 (75%), and GF-17 (33%), while RI-10 and 17BIPHE2 are essentially randomly coiled (helix%: 7–10%). These results imply an important role for the additional N-terminal amino acids (likely E16) of SK-24 in stabilizing the helical conformation in PBS. It is proposed herein that SK-24 contains the minimal sequence for effective oligomerization of LL-37. Superior to LL-37 and RI-10, SK-24 shows an antimicrobial activity spectrum comparable to the major antimicrobial peptides GF-17 and GI-20 by targeting bacterial membranes and forming a helical conformation. Like the engineered peptide 17BIPHE2, SK-24 has a stronger antibiofilm activity than LL-37, GI-20, and GF-17. Nevertheless, SK-24 is least hemolytic at 200 µM compared with LL-37 and its other peptides investigated herein. Combined, these results enabled us to appreciate the elegance of the long amphipathic helix SK-24 nature deploys within LL-37 for human antimicrobial defense. SK-24 may be a useful template of therapeutic potential.
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Yason, John Anthony, Sitara Swarna Rao Ajjampur, and Kevin Shyong Wei Tan. "Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37." Infection and Immunity 84, no. 8 (May 23, 2016): 2220–32. http://dx.doi.org/10.1128/iai.00339-16.
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Blastocystisis one of the most common eukaryotic organisms found in humans and many types of animals. Several reports have identified its role in gastrointestinal disorders, although its pathogenicity is yet to be clarified.Blastocystisis transmitted via the fecal-to-oral route and colonizes the large intestines. Epithelial cells lining the intestine secrete antimicrobial peptides (AMPs), including beta-defensins and cathelicidin, as a response to infection. This study explores the effects of host colonic antimicrobial peptides, particularly LL-37, a fragment of cathelicidin, on differentBlastocystissubtypes.Blastocystisis composed of several subtypes that have genetic, metabolic, and biological differences. These subtypes also have various outcomes in terms of drug treatment and immune response. In this study,Blastocystisisolates from three different subtypes were found to induce intestinal epithelial cells to secrete LL-37. We also show that among the antimicrobial peptides tested, only LL-37 has broad activity on all the subtypes. LL-37 causes membrane disruption and causesBlastocystisto change shape.Blastocystissubtype 7 (ST7), however, showed relative resistance to LL-37. An isolate, ST7 isolate B (ST7-B), from this subtype releases proteases that can degrade the peptide. It also makes the environment acidic, which causes attenuation of LL-37 activity. TheBlastocystisST7-B isolate was also observed to have a thicker surface coat, which may protect the parasite from direct killing by LL-37. This study determined the effects of LL-37 on differentBlastocystisisolates and indicates that AMPs have significant roles inBlastocystisinfections.
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Amagai, Ryo, Toshiya Takahashi, Hitoshi Terui, Taku Fujimura, Kenshi Yamasaki, Setsuya Aiba, and Yoshihide Asano. "The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors." International Journal of Molecular Sciences 24, no. 1 (January 3, 2023): 875. http://dx.doi.org/10.3390/ijms24010875.
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An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.
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Mirzaee, Malihe, Edita Holásková, Alžbeta Mičúchová, David J. Kopečný, Zhila Osmani, and Ivo Frébort. "Long-Lasting Stable Expression of Human LL-37 Antimicrobial Peptide in Transgenic Barley Plants." Antibiotics 10, no. 8 (July 23, 2021): 898. http://dx.doi.org/10.3390/antibiotics10080898.
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Antimicrobial peptides play a crucial role in the innate immune system of multicellular organisms. LL-37 is the only known member of the human cathelicidin family. As well as possessing antibacterial properties, it is actively involved in various physiological responses in eukaryotic cells. Accordingly, there is considerable interest in large-scale, low-cost, and microbial endotoxin-free production of LL-37 recombinant peptides for pharmaceutical applications. As a heterologous expression biofactory, we have previously obtained homologous barley (Hordeum vulgare L.) as an attractive vehicle for producing recombinant human LL-37 in the grain storage compartment, endosperm. The long-term stability of expression and inheritance of transgenes is necessary for the successful commercialization of recombinant proteins. Here, we report the stable inheritance and expression of the LL-37 gene in barley after six generations, including two consecutive seasons of experimental field cultivation. The transgenic plants showed normal growth and remained fertile. Based on the bacteria viability test, the produced peptide LL-37 retained high antibacterial activity.
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Chawla, Himika, Parmita Kar, Soma Saha, Urvashi B. Singh, Nikhil Tandon, and Goswami R. "Circulating Antimicrobial Peptide LL-37 Status in Type 1 Diabetes Mellitus and its Relation with Glycemic Control." Annals of the National Academy of Medical Sciences (India) 53, no. 02 (April 2017): 066–72. http://dx.doi.org/10.1055/s-0040-1712747.
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ABSTRACTAntimicrobial-peptides are important molecules of constitutive innate immunity. Though patients with diabetes mellitus are generally prone to infections, there is limited information on their antimicrobialpeptide status. We assessed the circulating LL-37 antimicrobial peptide (also referred as cathelicidin) levels in patients with type 1 diabetes mellitus and its relation with their glycemic status. The LL-37 mRNAexpression was assessed in the peripheral blood mononuclear cells (PBMC) by quantitative RTPCR using ß-actin and cytochrome-C1 as the reference genes in 154 subjects (Type 1 diabetes, n=111 and healthy subjects, n=43). Serum LL-37 was quantified using sandwich-ELISA. Average HbA1c over last 2 years and current HbA1c were used to determine long-term and short-term glycemic status. LL-37 mRNAexpression and serum LL-37 levels were correlated with the glycemic status. The LL-37 mRNA copies were comparable between type 1 diabetes and healthy subjects [median (IQR) = 6.7 (1.8–15.28) vs. 7.2 (2.23–21.86), respectively, P = 0.42]. There was no significant difference in serum LL-37 levels between the two groups [median (IQR) = 3.9 (2.88–7.52) vs. 5.0 (3.19–9.05) ng/ml, respectively, P = 0.52]. The LL-37 mRNA and its protein concentration showed no significant correlation with the average or current HbA1c values. The constitutive circulating antimicrobial peptide LL-37 status is not significantly altered in patients with type 1 diabetes mellitus and also not affected by their glycemic status.
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Turner, Jeffrey, Yoon Cho, Nhu-Nguyen Dinh, Alan J. Waring, and Robert I. Lehrer. "Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils." Antimicrobial Agents and Chemotherapy 42, no. 9 (September 1, 1998): 2206–14. http://dx.doi.org/10.1128/aac.42.9.2206.
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ABSTRACT Human neutrophils contain two structurally distinct types of antimicrobial peptides, β-sheet defensins (HNP-1 to HNP-4) and the α-helical peptide LL-37. We used radial diffusion assays and an improved National Committee for Clinical Laboratory Standards-type broth microdilution assay to compare the antimicrobial properties of LL-37, HNP-1, and protegrin (PG-1). Although generally less potent than PG-1, LL-37 showed considerable activity (MIC, <10 μg/ml) againstPseudomonas aeruginosa, Salmonella typhimurium,Escherichia coli, Listeria monocytogenes,Staphylococcus epidermidis, Staphylococcus aureus, and vancomycin-resistant enterococci, even in media that contained 100 mM NaCl. Certain organisms (methicillin-resistantS. aureus, Proteus mirabilis, and Candida albicans) were resistant to LL-37 in media that contained 100 mM NaCl but were susceptible in low-salt media. Burkholderia cepacia was resistant to LL-37, PG-1, and HNP-1 in low- or high-salt media. LL-37 caused outer and inner membrane permeabilization of E. coli ML-35p. Chromogenic Limulus assays revealed that LL-37 bound to E. coli O111:B4 lipopolysaccharide (LPS) with a high affinity and that this binding showed positive cooperativity (Hill coefficient = 2.02). Circular dichroism spectrometry disclosed that LL-37 underwent conformational change in the presence of lipid A, transitioning from a random coil to an α-helical structure. The broad-spectrum antimicrobial properties of LL-37, its presence in neutrophils, and its inducibility in keratinocytes all suggest that this peptide and its precursor (hCAP-18) may protect skin and other tissues from bacterial intrusions and LPS-induced toxicity. The potent activity of LL-37 againstP. aeruginosa, including mucoid and antibiotic-resistant strains, suggests that it or related molecules might have utility as topical bronchopulmonary microbicides in cystic fibrosis.
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Hase, Koji, Lars Eckmann, John D. Leopard, Nissi Varki, and Martin F. Kagnoff. "Cell Differentiation Is a Key Determinant of Cathelicidin LL-37/Human Cationic Antimicrobial Protein 18 Expression by Human Colon Epithelium." Infection and Immunity 70, no. 2 (February 2002): 953–063. http://dx.doi.org/10.1128/iai.70.2.953-963.2002.
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ABSTRACT Antimicrobial peptides are highly conserved evolutionarily and are thought to play an important role in innate immunity at intestinal mucosal surfaces. To better understand the role of the antimicrobial peptide human cathelicidin LL-37/human cationic antimicrobial protein 18 (hCAP18) in intestinal mucosal defense, we characterized the regulated expression and production of this peptide by human intestinal epithelium. LL-37/hCAP18 is shown to be expressed within epithelial cells located at the surface and upper crypts of normal human colon. Little or no expression was seen within the deeper colon crypts or within epithelial cells of the small intestine. Paralleling its expression in more differentiated epithelial cells in vivo, LL-37/hCAP18 mRNA and protein expression was upregulated in spontaneously differentiating Caco-2 human colon epithelial cells and in HCA-7 human colon epithelial cells treated with the cell differentiation-inducing agent sodium butyrate. LL-37/hCAP18 expression by colon epithelium does not require commensal bacteria, since LL-37/hCAP18 is produced with a similar expression pattern by epithelial cells in human colon xenografts that lack a luminal microflora. LL-37/hCAP18 mRNA was not upregulated in response to tumor necrosis factor alpha, interleukin 1α (IL-1α), gamma interferon, lipopolysaccharide, or IL-6, nor did the expression patterns and levels of LL-37/hCAP18 in the epithelium of the normal and inflamed colon differ. On the other hand, infection of HCA-7 cells with Salmonella enterica serovar Dublin or enteroinvasive Escherichia coli modestly upregulated LL-37/hCAP18 mRNA expression. We conclude that differentiated human colon epithelium expresses LL-37/hCAP18 as part of its repertoire of innate defense molecules and that the distribution and regulated expression of LL-37/hCAP18 in the colon differs markedly from that of other enteric antimicrobial peptides, such as defensins.
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Guo, Fang-Fang, and Jing-Yuan Fang. "Antimicrobial peptide LL-37 and gastrointestinal diseases." World Chinese Journal of Digestology 22, no. 35 (2014): 5454. http://dx.doi.org/10.11569/wcjd.v22.i35.5454.
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Bucki, Robert, Katarzyna Leszczyńska, Andrzej Namiot, and Wojciech Sokołowski. "Cathelicidin LL-37: A Multitask Antimicrobial Peptide." Archivum Immunologiae et Therapiae Experimentalis 58, no. 1 (January 5, 2010): 15–25. http://dx.doi.org/10.1007/s00005-009-0057-2.
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Marr, A. K., S. Cen, R. E. W. Hancock, and W. R. McMaster. "Identification of Synthetic and Natural Host Defense Peptides with Leishmanicidal Activity." Antimicrobial Agents and Chemotherapy 60, no. 4 (February 16, 2016): 2484–91. http://dx.doi.org/10.1128/aac.02328-15.
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ABSTRACTLeishmaniaparasites are a major public health problem worldwide. Effective treatment of leishmaniasis is hampered by the high incidence of adverse effects to traditional drug therapy and the emergence of resistance to current therapeutics. A vaccine is currently not available. Host defense peptides have been investigated as novel therapeutic agents against a wide range of pathogens. Here we demonstrate that the antimicrobial peptide LL-37 and the three synthetic peptides E6, L-1018, and RI-1018 exhibit leishmanicidal activity against promastigotes and intramacrophage amastigotes ofLeishmania donovaniandLeishmania major. We also report that theLeishmaniaprotease/virulence factor GP63 confers protection toLeishmaniafrom the cytolytic properties of alll-form peptides (E6, L-1018, and LL-37) but not thed-form peptide RI-1018. The results suggest that RI-1018, E6, and LL-37 are promising peptides to develop further into components for antileishmanial therapy.
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Zhao, Chengquan, Tung Nguyen, Lee Ming Boo, Teresa Hong, Cesar Espiritu, Dmitri Orlov, Wei Wang, Alan Waring, and Robert I. Lehrer. "RL-37, an Alpha-Helical Antimicrobial Peptide of the Rhesus Monkey." Antimicrobial Agents and Chemotherapy 45, no. 10 (October 1, 2001): 2695–702. http://dx.doi.org/10.1128/aac.45.10.2695-2702.2001.
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ABSTRACT Rhesus monkey bone marrow expresses a cathelicidin whose C-terminal domain comprises a 37-residue alpha-helical peptide (RL-37) that resembles human LL-37. Like its human counterpart, RL-37 rapidly permeabilized the membranes of Escherichia coli ML-35p and lysed liposomes that simulated bacterial membranes. When tested in media whose NaCl concentrations approximated those of extracellular fluids, RL-37 was considerably more active than LL-37 against staphylococci. Whereas human LL-37 contains five acidic residues and has a net charge of +6, rhesus RL-37 has only two acidic residues and a net charge of +8. Speculating that the multiple acidic residues of human LL-37 reduced its efficacy against staphylococci, we made a peptide (LL-37 pentamide) in which each aspartic acid of LL-37 was replaced by an asparagine and each glutamic acid was replaced by a glutamine. LL-37 pentamide's antistaphylococcal activity was substantially greater than that of LL-37. Thus, although the precursor of LL-37 is induced in human skin keratinocytes by injury or inflammation, its insufficiently cationic antimicrobial domain may contribute to the success of staphylococci in colonizing and infecting human skin.
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Shaykhiev, Renat, Christoph Beißwenger, Kerstin Kändler, Judith Senske, Annette Püchner, Thomas Damm, Jürgen Behr, and Robert Bals. "Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 5 (November 2005): L842—L848. http://dx.doi.org/10.1152/ajplung.00286.2004.
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Antimicrobial peptides are endogenous antibiotics that directly inactivate microorganisms and in addition have a variety of receptor-mediated functions. LL-37/hCAP-18 is the only cathelicidin found in humans and is involved in angiogenesis and regulation of the innate immune system. The aim of the present study was to characterize the role of the peptide LL-37 in the regulation of wound closure of the airway epithelium in the cell line NCI-H292 and primary airway epithelial cells. LL-37 stimulated healing of mechanically induced wounds in monolayers of the cell line and in differentiated primary airway epithelium. This effect was detectable at concentrations of 5 μg/ml in NCI-H292 and 1 μg/ml in primary cells. The effect of LL-37 on wound healing was dependent on the presence of serum. LL-37 induced cell proliferation and migration of NCI-H292 cells. Inhibitor studies in the wound closure and proliferation assays indicated that the effects caused by LL-37 are mediated through epidermal growth factor receptor, a G protein-coupled receptor, and MAP/extracellular regulated kinase. In conclusion, LL-37 induces wound healing, proliferation, and migration of airway epithelial cells. The peptide is likely involved in the regulation of tissue homeostasis in the airways.
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Sol, Asaf, Ofir Ginesin, Stella Chaushu, Laila Karra, Shunit Coppenhagen-Glazer, Isaac Ginsburg, and Gilad Bachrach. "LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations." Infection and Immunity 81, no. 10 (July 8, 2013): 3577–85. http://dx.doi.org/10.1128/iai.01288-12.
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ABSTRACTHost defense peptides are immediate responders of the innate immunity that express antimicrobial, immunoregulatory, and wound-healing activities. Neutrophils are a major source for oral host defense peptides, and phagocytosis by neutrophils is a major mechanism for bacterial clearance in the gingival tissue. Dysfunction of or reduction in the numbers of neutrophils or deficiency in the LL-37 host defense peptide was each previously linked with proliferation of oralAggregatibacter actinomycetemcomitanswhich resulted in an aggressive periodontal disease. Surprisingly,A. actinomycetemcomitansshows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation byA. actinomycetemcomitansand act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake ofA. actinomycetemcomitansby neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing ofA. actinomycetemcomitansby murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. AlthoughA. actinomycetemcomitansis resistant to the bactericidal effect of LL-37, our results offer a rationale for the epidemiological association between LL-37 deficiency and the expansion of oralA. actinomycetemcomitansand indicate a possible therapeutic use of cationic peptides for host defense.
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Gutner, Michal, Stella Chaushu, Daniela Balter, and Gilad Bachrach. "Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis." Infection and Immunity 77, no. 12 (October 5, 2009): 5558–63. http://dx.doi.org/10.1128/iai.00648-09.
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ABSTRACT Proteolysis is a common microbial virulence mechanism that enables the destruction of host tissue and evasion from host defense mechanisms. Antimicrobial peptides, also known as host defense peptides, are effector molecules of the innate immunity that demonstrate a broad range of antimicrobial and immunoregulatory activities. Deficiency of the human LL-37 antimicrobial peptide was previously correlated with severe periodontal disease. Porphyromonas gingivalis, the major pathogen associated with periodontitis, is highly proteolytic. In this study, P. gingivalis was found capable of degrading LL-37 by utilizing its arginine-specific gingipains. Saliva collected from volunteers with a healthy periodontium protected LL-37 from proteolysis by P. gingivalis. Salivary protection of LL-37 was heat resistant and specific and enabled LL-37 to inhibit growth of Escherichia coli in the presence of the P. gingivalis proteases. Previously, saliva and other body fluids have been shown to inhibit the antimicrobial activity of LL-37. Here we demonstrate that at a cost of a small reduction in the bactericidal activity of LL-37, saliva enables the antibacterial activity of LL-37 despite the presence of proteases secreted by the main periodontopathogen.
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Rapala-Kozik, Maria, Oliwia Bochenska, Marcin Zawrotniak, Natalia Wolak, Grzegorz Trebacz, Mariusz Gogol, Dominika Ostrowska, Wataru Aoki, Mitsuyoshi Ueda, and Andrzej Kozik. "Inactivation of the Antifungal and Immunomodulatory Properties of Human Cathelicidin LL-37 by Aspartic Proteases Produced by the Pathogenic Yeast Candida albicans." Infection and Immunity 83, no. 6 (April 6, 2015): 2518–30. http://dx.doi.org/10.1128/iai.00023-15.
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Constant cross talk betweenCandida albicansyeast cells and their human host determines the outcome of fungal colonization and, eventually, the progress of infectious disease (candidiasis). An effective weapon used byC. albicansto cope with the host defense system is the release of 10 distinct secreted aspartic proteases (SAPs). Here, we validate a hypothesis that neutrophils and epithelial cells use the antimicrobial peptide LL-37 to inactivateC. albicansat sites of candidal infection and thatC. albicansuses SAPs to effectively degrade LL-37. LL-37 is cleaved into multiple products by SAP1 to -4, SAP8, and SAP9, and this proteolytic processing is correlated with the gradual decrease in the antifungal activity of LL-37. Moreover, a major intermediate of LL-37 cleavage—the LL-25 peptide—is antifungal but devoid of the immunomodulatory properties of LL-37. In contrast to LL-37, LL-25 did not affect the generation of reactive oxygen species by neutrophils upon treatment with phorbol esters. Stimulating neutrophils with LL-25 (rather than LL-37) significantly decreased calcium flux and interleukin-8 production, resulting in lower chemotactic activity of the peptide against neutrophils, which may decrease the recruitment of neutrophils to infection foci. LL-25 also lost the function of LL-37 as an inhibitor of neutrophil apoptosis, thereby reducing the life span of these defense cells. This study indicates thatC. albicanscan effectively use aspartic proteases to destroy the antimicrobial and immunomodulatory properties of LL-37, thus enabling the pathogen to survive and propagate.
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Wang, Guangshun, Karen M. Watson, and Robert W. Buckheit. "Anti-Human Immunodeficiency Virus Type 1 Activities of Antimicrobial Peptides Derived from Human and Bovine Cathelicidins." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 30, 2008): 3438–40. http://dx.doi.org/10.1128/aac.00452-08.
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ABSTRACT From among 15 human cathelicidin LL-37-derived peptides, FK-13 was identified as the smallest peptide active against human immunodeficiency virus (HIV) and GI-20 had the highest therapeutic index, which was twice that of LL-37. BMAP-18, which is derived from bovine cathelicidin BMAP-27, possessed a therapeutic index similar to that of GI-20. Peptide sequence order, helical structures, and aromatic residues are important in HIV inhibition.
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Kumagai, Yumi, Taisuke Murakami, Kuwahara-Arai, Toshiaki Iba, Johannes Reich, and Isao Nagaoka. "Antimicrobial peptide LL-37 ameliorates a murine sepsis model via the induction of microvesicle release from neutrophils." Innate Immunity 26, no. 7 (June 29, 2020): 565–79. http://dx.doi.org/10.1177/1753425920936754.
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Sepsis is a life-threatening disease caused by systemic dys-regulated inflammatory response to infection. We previously revealed that LL-37, a human cathelicidin antimicrobial peptide, improves the survival of cecal ligation and puncture septic mice. Ectosomes, microvesicles released from neutrophils, are reported to be elevated in sepsis survivors; however, the functions of ectosomes in sepsis remain largely unknown. Therefore, we herein elucidated the protective action of LL-37 on sepsis, by focusing on LL-37-induced ectosome release in a cecal ligation and puncture model. The results demonstrated the enhancement of ectosome levels by LL-37 administration, accompanied by a reduction of bacterial load. Importantly, ectosomes isolated from LL-37-injected cecal ligation and puncture mice contained higher amounts of antimicrobial proteins/peptides and exhibited higher antibacterial activity, compared with those from PBS-injected cecal ligation and puncture mice, suggesting that LL-37 induces the release of ectosomes with antibacterial potential in vivo. Actually, LL-37 stimulated mouse bone-marrow neutrophils to release ectosomes ex vivo, and the LL-37-induced ectosomes possessed antibacterial potential. Furthermore, administration of LL-37-induced ectosomes reduced the bacterial load and improved the survival of cecal ligation and puncture mice. Together these observations suggest LL-37 induces the release of antimicrobial ectosomes in cecal ligation and puncture mice, thereby reducing the bacterial load and protecting mice from lethal septic conditions.
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Rosen, Graciela, Michael N. Sela, and Gilad Bachrach. "The Antibacterial Activity of LL-37 against Treponema denticola Is Dentilisin Protease Independent and Facilitated by the Major Outer Sheath Protein Virulence Factor." Infection and Immunity 80, no. 3 (December 19, 2011): 1107–14. http://dx.doi.org/10.1128/iai.05903-11.
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Host defense peptides are innate immune effectors that possess both bactericidal activities and immunomodulatory functions. Deficiency in the human host defense peptide LL-37 has previously been correlated with severe periodontal disease.Treponema denticolais an oral anaerobic spirochete closely associated with the pathogenesis of periodontal disease. TheT. denticolamajor surface protein (MSP), involved in adhesion and cytotoxicity, and the dentilisin serine protease are key virulence factors of this organism. In this study, we examined the interactions between LL-37 andT. denticola. The threeT. denticolastrains tested were susceptible to LL-37. Dentilisin was found to inactivate LL-37 by cleaving it at the Lys, Phe, Gln, and Val residues. However, dentilisin deletion did not increase the susceptibility ofT. denticolato LL-37. Furthermore, dentilisin activity was found to be inhibited by human saliva. In contrast, a deficiency of theT. denticolaMSP increased resistance to LL-37. The MSP-deficient mutant bound less fluorescently labeled LL-37 than the wild-type strain. MSP demonstrated specific, dose-dependent LL-37 binding. In conclusion, though capable of LL-37 inactivation, dentilisin does not protectT. denticolafrom LL-37. Rather, the rapid, MSP-mediated binding of LL-37 to the treponemal outer sheath precedes cleavage by dentilisin. Moreover,in vivo, saliva inhibits dentilisin, thus preventing LL-37 restriction and ensuring its bactericidal and immunoregulatory activities.
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Johansson, Linda, Pontus Thulin, Parham Sendi, Erika Hertzén, Adam Linder, Per Åkesson, Donald E. Low, Birgitta Agerberth, and Anna Norrby-Teglund. "Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans." Infection and Immunity 76, no. 8 (May 19, 2008): 3399–404. http://dx.doi.org/10.1128/iai.01392-07.
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ABSTRACT Severe soft tissue infections, such as necrotizing fasciitis and severe cellulitis, caused by group A streptococci (GAS) are rapidly progressing life-threatening infections characterized by massive bacterial loads in the tissue even late after the onset of infection. Antimicrobial peptides are important components of the innate host defense, and cathelicidins have been shown to protect against murine necrotic skin infections caused by GAS. However, it has been demonstrated that the streptococcal cysteine protease SpeB proteolytically inactivates the human cathelicidin LL-37 in vitro. Here we have investigated the expression of LL-37 and its interaction with GAS and SpeB during acute severe soft tissue infections by analyses of patient tissue biopsy specimens. The results showed large amounts of LL-37, both the proform (hCAP18) and the mature peptide, in the tissue. Confocal microscopy identified neutrophils as the main source of the peptide. A distinct colocalization between the bacteria and LL-37 could be noted, and bacterial loads showed positive correlation to the LL-37 levels. Areas with high LL-37 levels coincided with areas with large amounts of SpeB. Confocal microscopy confirmed strong colocalization of GAS, SpeB, and LL-37 at the bacterial surface. Taken together, the findings of this study provide in vivo support of the hypothesis that SpeB-mediated inactivation of LL-37 at the streptococcal surface represents a bacterial resistance mechanism at the infected tissue site in patients with severe GAS tissue infections.
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Yusuf, Muhammad, Wanda Destiarani, Ade Rizqi Ridwan Firdaus, Fauzian Giansyah Rohmatulloh, Mia Tria Novianti, Gita Widya Pradini, and Reiva Farah Dwiyana. "Residual Interactions of LL-37 with POPC and POPE:POPG Bilayer Model Studied by All-Atom Molecular Dynamics Simulation." International Journal of Molecular Sciences 23, no. 21 (November 2, 2022): 13413. http://dx.doi.org/10.3390/ijms232113413.
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LL-37 is a membrane-active antimicrobial peptide (AMP) that could disrupt the integrity of bacterial membranes due to its inherent cationic and amphipathic nature. Developing a shorter derivative of a long peptide such as LL-37 is of great interest, as it can reduce production costs and cytotoxicity. However, more detailed information about the residual interaction between LL-37 and the membrane is required for further optimization. Previously, molecular dynamics simulation using mixed all-atom and united-atom force fields showed that LL-37 could penetrate the bilayer membrane. This study aimed to perform all-atom molecular dynamics simulations, highlighting the residual interaction of LL-37 with the simplest model of the bacterial membrane, POPE:POPG (2:1), and compare its interaction with the POPC, which represents the eukaryotic membrane. The result showed leucine–leucine as the leading residues of LL-37 that first contact the membrane surface. Then, the cationic peptide of LL-37 started to penetrate the membrane by developing salt bridges between positively charged amino acids, Lys–Arg, and the exposed phosphate group of POPE:POPG, which is shielded in POPC. Residues 18 to 29 are suggested as the core region of LL-37, as they actively interact with the POPE:POPG membrane, not POPC. These results could provide a basis for modifying the amino acid sequence of LL-37 and developing a more efficient design for LL-37 derivatives.
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OREN, Ziv, Jeffrey C. LERMAN, Gudmundur H. GUDMUNDSSON, Birgitta AGERBERTH, and Yechiel SHAI. "Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity." Biochemical Journal 341, no. 3 (July 26, 1999): 501–13. http://dx.doi.org/10.1042/bj3410501.
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The antimicrobial peptide LL-37 belongs to the cathelicidin family and is the first amphipathic α-helical peptide isolated from human. LL-37 is considered to play an important role in the first line of defence against local infection and systemic invasion of pathogens at sites of inflammation and wounds. Understanding its mode of action may assist in the development of antimicrobial agents mimicking those of the human immune system. In vitrostudies revealed that LL-37 is cytotoxic to both bacterial and normal eukaryotic cells. To gain insight into the mechanism of its non-cell-selective cytotoxicity, we synthesized and structurally and functionally characterized LL-37, its N-terminal truncated form FF-33, and their fluorescent derivatives (which retained structure and activity). The results showed several differences, between LL-37 and other native antimicrobial peptides, that may shed light on its in vivoactivities. Most interestingly, LL-37 exists in equilibrium between monomers and oligomers in solution at very low concentrations. Also, it is significantly resistant to proteolytic degradation in solution, and when bound to both zwitterionic (mimicking mammalian membranes) and negatively charged membranes (mimicking bacterial membranes). The results also showed a role for the N-terminus in proteolytic resistance and haemolytic activity, but not in antimicrobial activity. The LL-37 mode of action with negatively charged membranes suggests a detergent-like effect via a ‘carpet-like’ mechanism. However, the ability of LL-37 to oligomerize in zwitterionic membranes might suggest the formation of a transmembrane pore in normal eukaryotic cells. To examine this possibility we used polarized attenuated total reflectance Fourier-transform infrared spectroscopy and found that the peptide is predominantly α-helical and oriented nearly parallel with the surface of zwitterionic-lipid membranes. This result does not support the channel-forming hypothesis, but rather it supports the detergent-like effect.
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Bals, Robert, Xiaorong Wang, Michael Zasloff, and James M. Wilson. "The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface." Proceedings of the National Academy of Sciences 95, no. 16 (August 4, 1998): 9541–46. http://dx.doi.org/10.1073/pnas.95.16.9541.
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The airway surface is an important host defense against pulmonary infection. Secretion of proteins with antimicrobial activity from epithelial cells onto the airway surface represents an important component of this innate immune system. Defensins are the best characterized epithelial-derived peptide antibiotics. A member of another family of peptide antibiotics called cathelicidins recently was identified from human bone marrow. We show in this paper that this human peptide named LL-37/hCAP-18 also may play a role in innate immunity of the human lung.In situhybridization localized high levels of LL-37/hCAP-18 RNA to surface epithelial cells of the conducting airway as well as serous and mucous cells of the submucosal glands. LL-37/hCAP-18 peptide with antimicrobial activity was partially purified from airway surface fluid from human lung and a human bronchial xenograft model. The synthetic peptide LL-37 demonstrated antibiotic activity against a number of Gram-negative and Gram-positive organisms includingPseudomonas aeruginosa; bacterial killing of LL-37 was sensitive to NaCl and was synergistic with lactoferrin and lysozyme. In summary, we show that LL-37/hCAP-18 is a peptide with broad antimicrobial activity that is secreted onto the airway surface from epithelial cells of the human lung.
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Jang, Yong-Suk, Sae-Hae Kim, Ha-Yan Lee, Jisang Park, and Kyung-Yeol Lee. "Formyl-peptide receptor 2-expressing cells in Peyer’s patch are closely associated with the regulation of antigen-specific mucosal immune induction (MUC4P.832)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 133.8. http://dx.doi.org/10.4049/jimmunol.192.supp.133.8.
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Abstract It is known that formyl peptide receptor-2 (FPR-2) acts as innate immune sensor through recognition of peptides derived from pathogens such as H. pylori and HIV, mitochondrial peptides, amyloidogenic peptide including serum amyloid A, and inflammatory response-associated peptides such as LL-37. However, the role of FPR-2-expressing cells in mucosal immune inductive area, Peyer’s patch (PP), is still unraveled yet. In this study, we identified the expression of FPR-2 in both M cells located in follicle-associated epithelium of PP and follicular dendritic cells (FDCs) localized in germinal center. In addition, the level of Cxcl13 and TGF-β gene transcripts in FDCs, which are closely associated with recruitment and differentiation of IgA-secreting B cells was substantially increased by treatment of cathelicidin LL-37, one of FPR-2 ligands. Moreover, enhanced immune induction was verified in vivo mouse system through monitoring the antigen-specific mucosal immunity after oral administration of LL-37-conjugated antigen. Treatment of LL-37 has also shown the immune modulatory effects such as recruitment of CD11c+ cells and IL-17-secreting cells together with activation of FPR-2-expressing cells. Collectively, this study suggests that FPR-2-expressing cells are associated with regulation of mucosal immune induction and LL-37 could be used as a modulator for the cells.
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Bryzek, Danuta, Anna Golda, Joanna Budziaszek, Dominik Kowalczyk, Alicia Wong, Ewa Bielecka, Priyanka Shakamuri, et al. "Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity." International Journal of Molecular Sciences 21, no. 23 (November 30, 2020): 9126. http://dx.doi.org/10.3390/ijms21239126.
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LL-37, the only member of the mammalian cathelicidin in humans, plays an essential role in innate immunity by killing pathogens and regulating the inflammatory response. However, at an inflammatory focus, arginine residues in LL-37 can be converted to citrulline via a reaction catalyzed by peptidyl-arginine deiminases (PAD2 and PAD4), which are expressed in neutrophils and are highly active during the formation of neutrophil extracellular traps (NETs). Citrullination impairs the bactericidal activity of LL-37 and abrogates its immunomodulatory functions. Therefore, we hypothesized that citrullination-resistant LL-37 variants would retain the functionality of the native peptide in the presence of PADs. To test this hypothesis, we synthetized LL-37 in which arginine residues were substituted by homoarginine (hArg-LL-37). Bactericidal activity of hArg-LL-37 was comparable with that of native LL-37, but neither treatment with PAD4 nor exposure to NETs affected the antibacterial and immunomodulatory activities of hArg-LL-37. Importantly, the susceptibilities of LL-37 and hArg-LL-37 to degradation by proteases did not significantly differ. Collectively, we demonstrated that citrullination-resistant hArg-LL-37 is an attractive lead compound for the generation of new agents to treat bacterial infections and other inflammatory diseases associated with enhanced PAD activity. Moreover, our results provide a proof-of-concept for synthesis of therapeutic peptides using homoarginine.
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Ciornei, Cristina D., Thorgerdur Sigurdardóttir, Artur Schmidtchen, and Mikael Bodelsson. "Antimicrobial and Chemoattractant Activity, Lipopolysaccharide Neutralization, Cytotoxicity, and Inhibition by Serum of Analogs of Human Cathelicidin LL-37." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2845–50. http://dx.doi.org/10.1128/aac.49.7.2845-2850.2005.
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ABSTRACT Antimicrobial peptides have been evaluated in vitro and in vivo as alternatives to conventional antibiotics. Apart from being antimicrobial, the native human cathelicidin-derived peptide LL-37 (amino acids [aa] 104 to 140 of the human cathelicidin antimicrobial peptide) also binds and neutralizes bacterial lipopolysaccharide (LPS) and might therefore have beneficial effects in the treatment of septic shock. However, clinical trials have been hampered by indications of toxic effects of LL-37 on mammalian cells and evidence that its antimicrobial effects are inhibited by serum. For the present study, LL-37 was compared to two less hydrophobic fragments obtained by N-terminal truncation, named 106 (aa 106 to 140) and 110 (aa 110 to 140), and to a previously described more hydrophobic variant, the 18-mer LLKKK, concerning antimicrobial properties, lipopolysaccharide neutralization, toxicity against human erythrocytes and cultured vascular smooth muscle cells, chemotactic activity, and inhibition by serum. LL-37, fragments 106 and 110, and the 18-mer LLKKK inhibited the growth of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans in a radial diffusion assay, inhibited lipopolysaccharide-induced vascular nitric oxide production, and attracted neutrophil granulocytes similarly. While fragments 106 and 110 caused less hemolysis and DNA fragmentation in cultured cells than did LL-37, the 18-mer LLKKK induced severe hemolysis. The antibacterial effect of fragments 106 and 110 was not affected by serum, while the effect of LL-37 was reduced. We concluded that the removal of N-terminal hydrophobic amino acids from LL-37 decreases its cytotoxicity as well as its inhibition by serum without negatively affecting its antimicrobial or LPS-neutralizing action. Such LL-37-derived peptides may thus be beneficial for the treatment of patients with sepsis.
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Ishvaanjil, Bayartbat, Yu-Jin Jung, Uyangaa Temuujin, Soon-Youl Lee, and Kwon-Kyoo Kang. "HETEROLOGOUS EXPRESSION OF ANTIMICROBIAL PEPTIDE LL-37 IN CHINESE CABBAGE WITH ENHANCED RESISTANCE TO PATHOGENS." Mongolian Journal of Agricultural Sciences 13, no. 2 (June 22, 2015): 124–30. http://dx.doi.org/10.5564/mjas.v13i2.531.
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The human antimicrobial peptide, LL-37 gene was overexpressed in Chinese cabbage ‘Osome’ (Brassica rapa) by Agrobacterium tumefaciens-mediated transformation. In order to increase the expression of the antimicrobial peptide, we used RolA intron sequence in front of the LL-37peptide gene. We confirmed the expression of LL-37 in cabbage by RT-PCR and Western Blot analysis. Four transgenic T1 plants were confirmed that LL-37 was expressed. Cabbages expressing the humanLL-37 gene were challenged by various plant pathogen. Transgenic cabbage plants overproducing human LL-37 are expected to possess a durable and wide-spectrum resistance against various pathogens.Mongolian Journal of Agricultural Sciences Vol.13(2) 2014: 124-130
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Zeth, Kornelius, and Enea Sancho-Vaello. "Structural Plasticity of LL-37 Indicates Elaborate Functional Adaptation Mechanisms to Bacterial Target Structures." International Journal of Molecular Sciences 22, no. 10 (May 14, 2021): 5200. http://dx.doi.org/10.3390/ijms22105200.
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The human cathelicidin LL-37 is a multifunctional peptide of the human innate immune system. Among the various functions of LL-37, its antimicrobial activity is important in controlling the microorganisms of the human body. The target molecules of LL-37 in bacteria include membrane lipids, lipopolysaccharides (LPS), lipoteichoic acid (LTA), proteins, DNA and RNA. In this mini-review, we summarize the entity of LL-37 structural data determined over the last 15 years and specifically discuss features implicated in the interactions with lipid-like molecules. For this purpose, we discuss partial and full-length structures of LL-37 determined in the presence of membrane-mimicking detergents. This constantly growing structural database is now composed of monomers, dimers, tetramers, and fiber-like structures. The diversity of these structures underlines an unexpected plasticity and highlights the conformational and oligomeric adaptability of LL-37 necessary to target different molecular scaffolds. The recent co-crystal structures of LL-37 in complex with detergents are particularly useful to understand how these molecules mimic lipids and LPS to induce oligomerization and fibrillation. Defined detergent binding sites provide deep insights into a new class of peptide scaffolds, widening our view on the fascinating world of the LL-37 structural factotum. Together, the new structures in their evolutionary context allow for the assignment of functionally conserved residues in oligomerization and target interactions. Conserved phenylalanine and arginine residues primarily mediate those interactions with lipids and LPS. The interactions with macromolecules such as proteins or DNA remain largely unexplored and open a field for future studies aimed at structures of LL-37 complexes. These complexes will then allow for the structure-based rational design of LL-37-derived peptides with improved antibiotic properties.
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Torossian, Alexander, Eugeniu Gurschi, Robert Bals, Timon Vassiliou, Hinnerk F. Wulf, and Artur Bauhofer. "Effects of the Antimicrobial Peptide LL-37 and Hyperthermic Preconditioning in Septic Rats." Anesthesiology 107, no. 3 (September 1, 2007): 437–41. http://dx.doi.org/10.1097/01.anes.0000278906.86815.eb.
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Background The authors tested the effects of LL-37 prophylaxis or therapy on the outcome after intraabdominal sepsis and examined whether hyperthermic preconditioning plus LL-37 therapy augments host immune response and improves survival. Methods A rat model of peritoneal contamination and infection (PCI) with human stool was used to simulate clinical conditions. In trial 1, the authors compared (1) PCI, (2) LL-37 prophylaxis (0.5 mg/kg, 12 h before PCI), and (3) LL-37 therapy (0.5 mg/kg, 1 h after PCI). In trial 2, the authors compared (1) PCI, (2) LL-37 therapy, (3) hyperthermic preconditioning (41 degrees C for 1 h, 24 h before PCI), and (4) LL-37 therapy and hyperthermic preconditioning. The primary endpoint was mortality at 120 h. In trial 2, secondary endpoints were systemic levels of tumor necrosis factor alpha, interleukin 6, macrophage inflammatory protein 2, and heat shock protein 70; leukocyte counts; and neutrophil granulocyte phagocytosis. Results In trial 1, 30% of the control group compared with 70% of the LL-37 therapy group survived, but 55% after LL-37 prophylaxis survived (P = 0.038). In trial 2, 38% of the controls, 67% of the LL-37 therapy, 59% of the hyperthermic preconditioned, and 90% of the hyperthermic preconditioned plus LL-37 therapy group survived (P = 0.01). LL-37 therapy plus hyperthermic preconditioning reduced proinflammatory cytokine concentrations after sepsis; specifically compared with controls, macrophage inflammatory protein-2 and interleukin-6 levels were 1.5 +/- 1.5 versus 11 +/- 6 pg/ml (P = 0.028) and 13 +/- 8 versus 86 +/- 31 pg/ml, (P = 0.015), respectively. Conclusions In this model of intraabdominal sepsis, LL-37 therapy improved outcome. Hyperthermic preconditioning per se was not successful, but in combination with LL-37 therapy, the survival rate after sepsis was increased and the proinflammatory cytokine response was downgraded.
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Ridyard, Kylen E., and Joerg Overhage. "The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent." Antibiotics 10, no. 6 (May 29, 2021): 650. http://dx.doi.org/10.3390/antibiotics10060650.
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The rise in antimicrobial resistant bacteria threatens the current methods utilized to treat bacterial infections. The development of novel therapeutic agents is crucial in avoiding a post-antibiotic era and the associated deaths from antibiotic resistant pathogens. The human antimicrobial peptide LL-37 has been considered as a potential alternative to conventional antibiotics as it displays broad spectrum antibacterial and anti-biofilm activities as well as immunomodulatory functions. While LL-37 has shown promising results, it has yet to receive regulatory approval as a peptide antibiotic. Despite the strong antimicrobial properties, LL-37 has several limitations including high cost, lower activity in physiological environments, susceptibility to proteolytic degradation, and high toxicity to human cells. This review will discuss the challenges associated with making LL-37 into a viable antibiotic treatment option, with a focus on antimicrobial resistance and cross-resistance as well as adaptive responses to sub-inhibitory concentrations of the peptide. The possible methods to overcome these challenges, including immobilization techniques, LL-37 delivery systems, the development of LL-37 derivatives, and synergistic combinations will also be considered. Herein, we describe how combination therapy and structural modifications to the sequence, helicity, hydrophobicity, charge, and configuration of LL-37 could optimize the antimicrobial and anti-biofilm activities of LL-37 for future clinical use.
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Hitchon, Carol A., Xiaobo Meng, Hani S. El Gabalawy, and Linda Larcombe. "Human host defence peptide LL37 and anti-cyclic citrullinated peptide antibody in early inflammatory arthritis." RMD Open 5, no. 1 (April 2019): e000874. http://dx.doi.org/10.1136/rmdopen-2018-000874.
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ObjectiveAntibodies to citrullinated peptides (anti-CCP) develop in individuals predisposed to rheumatoid arthritis (RA). Neutrophil extracellular traps are a major source of citrullinated antigens and the immunomodulatory host defence peptide LL-37. Vitamin D regulates LL-37 expression. This study assessed the associations of LL-37 and anti-CCP, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms in early inflammatory arthritis (EIA).MethodsSerum LL-37, 25-hydroxy-vitamin D (25OHvitD) and anti-CCP were measured by ELISA in treatment naïve EIA (n = 181). VDR single nucleotide polymorphisms (Fok1, Bsm1, Apa1, Taq1, Cdx-2) and HLADRB1 shared epitope (SE) alleles were detected by DNA amplification. Associations were tested in multivariable models. Median (25%, 75%) or percentiles are reported.ResultsParticipants (70 % female, age 56 [45, 66] years, disease activity score [DAS28ESR3var] 3.7 [2.8, 4.8], 41 % anti-CCP positive, 68 % RA) had low serum 25OHvitD; 20.5 nmol/L (13.9, 29.0). In multivariable models, controlling for age, sex, SE, smoking and vitamin D deficiency, LL37 level (top quartile) associated with anti-CCP seropositivity (OR 22; 95% CI 4 to 104).ConclusionsLevels of circulating LL-37 are associated with anti-CCP seropositivity. LL37 activity may be one mechanism linking infection and toxin exposure to anti-CCP generation.
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Haisma, Elisabeth M., Anna de Breij, Heelam Chan, Jaap T. van Dissel, Jan W. Drijfhout, Pieter S. Hiemstra, Abdoelwaheb El Ghalbzouri, and Peter H. Nibbering. "LL-37-Derived Peptides Eradicate Multidrug-Resistant Staphylococcus aureus from Thermally Wounded Human Skin Equivalents." Antimicrobial Agents and Chemotherapy 58, no. 8 (May 19, 2014): 4411–19. http://dx.doi.org/10.1128/aac.02554-14.
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ABSTRACTBurn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistantStaphylococcus aureus(MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains ofS. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria.
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Mücke, Pierre-Alexander, Sandra Maaß, Thomas P. Kohler, Sven Hammerschmidt, and Dörte Becher. "Proteomic Adaptation of Streptococcus pneumoniae to the Human Antimicrobial Peptide LL-37." Microorganisms 8, no. 3 (March 14, 2020): 413. http://dx.doi.org/10.3390/microorganisms8030413.
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Secreted antimicrobial peptides (AMPs) are an important part of the human innate immune system and prevent local and systemic infections by inhibiting bacterial growth in a concentration-dependent manner. In the respiratory tract, the cationic peptide LL-37 is one of the most abundant AMPs and capable of building pore complexes in usually negatively charged bacterial membranes, leading to the destruction of bacteria. However, the adaptation mechanisms of several pathogens to LL-37 are already described and are known to weaken the antimicrobial effect of the AMP, for instance, by repulsion, export or degradation of the peptide. This study examines proteome-wide changes in Streptococcus pneumoniae D39, the leading cause of bacterial pneumonia, in response to physiological concentrations of LL-37 by high-resolution mass spectrometry. Our data indicate that pneumococci may use some of the known adaptation mechanisms to reduce the effect of LL-37 on their physiology, too. Additionally, several proteins seem to be involved in resistance to AMPs which have not been related to this process before, such as the teichoic acid flippase TacF (SPD_1128). Understanding colonization- and infection-relevant adaptations of the pneumococcus to AMPs, especially LL-37, could finally uncover new drug targets to weaken the burden of this widespread pathogen.
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Bachrach, G., G. Chaushu, M. Zigmond, E. Yefenof, A. Stabholz, J. Shapira, J. Merrick, and S. Chaushu. "Salivary LL-37 Secretion in Individuals with Down Syndrome is Normal." Journal of Dental Research 85, no. 10 (October 2006): 933–36. http://dx.doi.org/10.1177/154405910608501012.
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Antimicrobial peptides play an important role in the innate immune response. Deficiency in salivary LL-37 antimicrobial peptide has been implicated in periodontitis in patients with morbus Kostman syndrome. Down syndrome is associated with periodontitis, diminished salivary flow, and salivary immunoglobulin deficiency. In the present study, levels of LL-37 and its hCAP18 precursor were measured in saliva samples from young individuals with Down syndrome and compared with levels in those from age-matched healthy controls. LL-37 and human cathelicidin antimicrobial protein (hCAP18) were detected in whole but not in parotid saliva. hCAP18 was more abundant than LL-37. The concentrations of salivary hCAP18 and LL-37 were found to be higher in individuals with Down syndrome than in healthy controls, but their secretion rates were similar. We concluded that, while the adaptive immunity of individuals with Down syndrome is impaired at the oral mucosa, the secretion rate of the LL-37 component of the innate immune system is normal.
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Byfield, Fitzroy J., Qi Wen, Katarzyna Leszczyńska, Alina Kułakowska, Zbigniew Namiot, Paul A. Janmey, and Robert Bucki. "Cathelicidin LL-37 peptide regulates endothelial cell stiffness and endothelial barrier permeability." American Journal of Physiology-Cell Physiology 300, no. 1 (January 2011): C105—C112. http://dx.doi.org/10.1152/ajpcell.00158.2010.
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LL-37 peptide is a multifunctional host defense molecule essential for normal immune responses to infection or tissue injury. In this study we assess the impact of LL-37 on endothelial stiffness and barrier permeability. Fluorescence microscopy reveals membrane localization of LL-37 after its incubation with human umbilical vein endothelial cells (HUVECs). A concentration-dependent increase in stiffness was observed in HUVECs, bovine aortic endothelial cells (BAECs), human pulmonary microvascular endothelial cells, and mouse aorta upon LL-37 (0.5–5 μM) addition. Stiffening of BAECs by LL-37 was blocked by P2X7 receptor antagonists and by the intracellular Ca2+ chelator BAPTA-AM. Increased cellular stiffness correlated with a decrease in permeability of HUVEC cell monolayers after LL-37 addition compared with nontreated cells, which was similar to the effect observed upon treatment with sphingosine 1-phosphate, and both treatments increased F-actin content in the cortical region of the cells. These results suggest that the antiinflammatory effect of LL-37 at the site of infection or injury involves an LL-37-mediated increase in cell stiffening that prevents increased pericellular permeability. Such a mechanism may help to maintain tissue fluid homeostasis.
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Bals, Robert, Daniel J. Weiner, A. David Moscioni, Rupalie L. Meegalla, and James M. Wilson. "Augmentation of Innate Host Defense by Expression of a Cathelicidin Antimicrobial Peptide." Infection and Immunity 67, no. 11 (November 1, 1999): 6084–89. http://dx.doi.org/10.1128/iai.67.11.6084-6089.1999.
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ABSTRACT Antimicrobial peptides, such as defensins or cathelicidins, are effector substances of the innate immune system and are thought to have antimicrobial properties that contribute to host defense. The evidence that vertebrate antimicrobial peptides contribute to innate immunity in vivo is based on their expression pattern and in vitro activity against microorganisms. The goal of this study was to investigate whether the overexpression of an antimicrobial peptide results in augmented protection against bacterial infection. C57BL/6 mice were given an adenovirus vector containing the cDNA for LL-37/hCAP-18, a human cathelicidin antimicrobial peptide. Mice treated with intratracheal LL-37/hCAP-18 vector had a lower bacterial load and a smaller inflammatory response than did untreated mice following pulmonary challenge with Pseudomonas aeruginosa PAO1. Systemic expression of LL-37/hCAP-18 after intravenous injection of recombinant adenovirus resulted in improved survival rates following intravenous injection of lipopolysaccharide with galactosamine or Escherichia coli CP9. In conclusion, the data demonstrate that expression of an antimicrobial peptide by gene transfer results in augmentation of the innate immune response, providing support for the hypothesis that vertebrate antimicrobial peptides protect against microorganisms in vivo.
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Martynowycz, Michael, Amy Rice, Konstantin Andreev, Thatyane M. Nobre Pavinatto, Jeff Wereszczynski, and David Gidalevitz. "Interaction of Antimicrobial Peptide Ll-37 with Lipopolysaccharides." Biophysical Journal 116, no. 3 (February 2019): 45a. http://dx.doi.org/10.1016/j.bpj.2018.11.285.
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McCrudden, Maelíosa, Katherine O’Donnell, Chris Irwin, and Fionnuala Lundy. "Effects of LL-37 on Gingival Fibroblasts: A Role in Periodontal Tissue Remodeling?" Vaccines 6, no. 3 (July 23, 2018): 44. http://dx.doi.org/10.3390/vaccines6030044.
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Mounting evidence suggests that the host defence peptide, LL-37, plays a role in both inflammation and in wound healing; however, the role of this peptide in the remodeling and maintenance of oral tissues is not yet fully understood. Fibroblasts are the most abundant cell type within the periodontal tissues, and gingival fibroblasts play an important role in maintaining and repairing the gingival tissues which are constantly exposed to external insults. In this study we examined the direct effects of LL-37 treatment on gingival fibroblasts and found that LL-37 significantly increased secretion of both interleukin 8 (IL-8) and IL-6 from these cells. LL-37 tended to decrease matrix metalloproteinase (MMP) activity in gingival fibroblasts, but this decrease did not reach statistical significance. LL-37 significantly increased tissue inhibitor of metalloproteinase-1 (TIMP-1) production by gingival fibroblasts, but had no significant effect on TIMP-2 levels. LL-37 was also shown to significantly increase production of basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) in gingival fibroblasts. Taken together, these results suggest an important role for the host defence peptide, LL-37, in modulating the fibroblast response to remodeling in periodontal tissues.
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Lysenko, Elena S., Jane Gould, Robert Bals, James M. Wilson, and Jeffrey N. Weiser. "Bacterial Phosphorylcholine Decreases Susceptibility to the Antimicrobial Peptide LL-37/hCAP18 Expressed in the Upper Respiratory Tract." Infection and Immunity 68, no. 3 (March 1, 2000): 1664–71. http://dx.doi.org/10.1128/iai.68.3.1664-1671.2000.
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ABSTRACT A number of pathogens of the upper respiratory tract express an unusual prokaryotic structure, phosphorylcholine (ChoP), on their cell surface. We tested the hypothesis that ChoP, also found on host membrane lipids in the form of phosphatidylcholine, acts so as to decrease killing by antimicrobial peptides that target differences between bacterial and host membranes. In Haemophilus influenzae, ChoP is a phase-variable structure on the oligosaccharide portion of the lipopolysaccharide (LPS). There was a bactericidal effect of the peptide LL-37/hCAP18 on a nontypeableH. influenzae strain, with an increasing selection for the ChoP+ phase as the concentration of the peptide was raised from 0 to 10 μg/ml. Moreover, constitutive ChoP-expressing mutants of unrelated strains showed up to 1,000-fold-greater survival compared to mutants without ChoP. The effect of ChoP on resistance to killing by LL-37/hCAP18 was dependent on the salt concentration and was observed only when bacteria were grown in the presence of environmental choline, a requirement for the expression of ChoP on the LPS. Further studies established that there is transcription of the LL-37/hCAP18 gene on the epithelial surface of the human nasopharynx in situ and inducible transcription in epithelial cells derived from the upper airway. The presence of highly variable amounts of LL-37/hCAP18 in normal nasal secretions (<1.2 to >80 μg/ml) was demonstrated with an antibody against this peptide. It was concluded that ChoP alters the bacterial cell surface so as mimic host membrane lipids and decrease killing by LL-37/hCAP18, an antimicrobial peptide that may be expressed on the mucosal surface of the nasopharynx in bactericidal concentrations.
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Nagaoka, Isao, Satoko Hirota, François Niyonsaba, Michimasa Hirata, Yoshiyuki Adachi, Hiroshi Tamura, Shigenori Tanaka, and Didier Heumann. "Augmentation of the Lipopolysaccharide-Neutralizing Activities of Human Cathelicidin CAP18/LL-37-Derived Antimicrobial Peptides by Replacement with Hydrophobic and Cationic Amino Acid Residues." Clinical and Vaccine Immunology 9, no. 5 (September 2002): 972–82. http://dx.doi.org/10.1128/cdli.9.5.972-982.2002.
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ABSTRACT Mammalian myeloid and epithelial cells express various peptide antibiotics (such as defensins and cathelicidins) that contribute to the innate host defense against invading microorganisms. Among these peptides, human cathelicidin CAP18/LL-37 (L1 to S37) possesses not only potent antibacterial activity against gram-positive and gram-negative bacteria but also the ability to bind to gram-negative lipopolysaccharide (LPS) and neutralize its biological activities. In this study, to develop peptide derivatives with improved LPS-neutralizing activities, we utilized an 18-mer peptide (K15 to V32) of LL-37 as a template and evaluated the activities of modified peptides by using the CD14+ murine macrophage cell line RAW 264.7 and the murine endotoxin shock model. By replacement of E16 and K25 with two L residues, the hydrophobicity of the peptide (18-mer LL) was increased, and by further replacement of Q22, D26, and N30 with three K residues, the cationicity of the peptide (18-mer LLKKK) was enhanced. Among peptide derivatives, 18-mer LLKKK displayed the most powerful LPS-neutralizing activity: it was most potent at binding to LPS, inhibiting the interaction between LPS and LPS-binding protein, and attaching to the CD14 molecule, thereby suppressing the binding of LPS to CD14+ cells and attenuating production of tumor necrosis factor alpha (TNF-α) by these cells. Furthermore, in the murine endotoxin shock model, 18-mer LLKKK most effectively suppressed LPS-induced TNF-α production and protected mice from lethal endotoxin shock. Together, these observations indicate that the LPS-neutralizing activities of the amphipathic human CAP18/LL-37-derived 18-mer peptide can be augmented by modifying its hydrophobicity and cationicity, and that 18-mer LLKKK is the most potent of the peptide derivatives, with therapeutic potential for gram-negative bacterial endotoxin shock.
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Chung, Myung-Chul, Scott N. Dean, and Monique L. van Hoek. "Acyl carrier protein is a bacterial cytoplasmic target of cationic antimicrobial peptide LL-37." Biochemical Journal 470, no. 2 (August 20, 2015): 243–53. http://dx.doi.org/10.1042/bj20150432.
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In addition to membrane disruption, the cathelicidin antimicrobial peptide LL-37 translocates through the bacterial inner membrane to target intracellular molecules. Our data suggest that the CAMP LL-37 is able can specifically bind to the cytoplasmic protein AcpP resulting in the inhibition of fatty acid synthesis and bacterial killing. Our studies introduce a novel mechanism for cationic antimicrobial peptides, which may be useful in future drug development for the treatment of antibiotic-resistant bacterial infection.
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Deshpande, Dhruva, Mark Grieshober, Fanny Wondany, Fabian Gerbl, Reiner Noschka, Jens Michaelis, and Steffen Stenger. "Super-Resolution Microscopy Reveals a Direct Interaction of Intracellular Mycobacterium tuberculosis with the Antimicrobial Peptide LL-37." International Journal of Molecular Sciences 21, no. 18 (September 14, 2020): 6741. http://dx.doi.org/10.3390/ijms21186741.
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The antimicrobial peptide LL-37 inhibits the growth of the major human pathogen Mycobacterium tuberculosis (Mtb), but the mechanism of the peptide–pathogen interaction inside human macrophages remains unclear. Super-resolution imaging techniques provide a novel opportunity to visualize these interactions on a molecular level. Here, we adapt the super-resolution technique of stimulated emission depletion (STED) microscopy to study the uptake, intracellular localization and interaction of LL-37 with macrophages and virulent Mtb. We demonstrate that LL-37 is internalized by both uninfected and Mtb infected primary human macrophages. The peptide localizes in the membrane of early endosomes and lysosomes, the compartment in which mycobacteria reside. Functionally, LL-37 disrupts the cell wall of intra- and extracellular Mtb, resulting in the killing of the pathogen. In conclusion, we introduce STED microscopy as an innovative and informative tool for studying host–pathogen–peptide interactions, clearly extending the possibilities of conventional confocal microscopy.
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Lau, Y. Elaine, Annett Rozek, Monisha G. Scott, Danika L. Goosney, Donald J. Davidson, and Robert E. W. Hancock. "Interaction and Cellular Localization of the Human Host Defense Peptide LL-37 with Lung Epithelial Cells." Infection and Immunity 73, no. 1 (January 2005): 583–91. http://dx.doi.org/10.1128/iai.73.1.583-591.2005.
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ABSTRACT LL-37 is a human cationic host defense peptide that is an essential component of innate immunity. In addition to its modest antimicrobial activity, LL-37 affects the gene expression and behavior of effector cells involved in the innate immune response, although its mode of interaction with eukaryotic cells remains unclear. The interaction of LL-37 with epithelial cells was characterized in tissue culture by using biotinylated LL-37 and confocal microscopy. It was demonstrated that LL-37 was actively taken up into A549 epithelial cells and eventually localized to the perinuclear region. Specific inhibitors were used to demonstrate that the uptake process was not mediated by actin but required elements normally involved in endocytosis and that trafficking to the perinuclear region was dependent on microtubules. By using nonlinear regression analysis, it was revealed that A549 epithelial cells have two receptors for LL-37B, with high and low affinity for LL-37, respectively. These results indicate the mode of interaction of LL-37 with epithelial cells and further our understanding of its role in modulating the innate immune response.
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Chen, Xi, Xianqiong Zou, Guangying Qi, Ying Tang, Yong Guo, Jia Si, and Lihua Liang. "Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer." Cellular Physiology and Biochemistry 47, no. 3 (2018): 1060–73. http://dx.doi.org/10.1159/000490183.
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LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.
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Noore, Jabeen, Adly Noore, and Bingyun Li. "Cationic Antimicrobial Peptide LL-37 Is Effective against both Extra- and Intracellular Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 28, 2012): 1283–90. http://dx.doi.org/10.1128/aac.01650-12.
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ABSTRACTThe increasing resistance of bacteria to conventional antibiotics and the challenges posed by intracellular bacteria, which may be responsible for chronic and recurrent infections, have driven the need for advanced antimicrobial drugs for effective elimination of both extra- and intracellular pathogens. The purpose of this study was to determine the killing efficacy of cationic antimicrobial peptide LL-37 compared to conventional antibiotics against extra- and intracellularStaphylococcus aureus. Bacterial killing assays and an infection model of osteoblasts andS. aureuswere studied to determine the bacterial killing efficacy of LL-37 and conventional antibiotics against extra- and intracellularS. aureus. We found that LL-37 was effective in killing extracellularS. aureusat nanomolar concentrations, while lactoferricin B was effective at micromolar concentrations and doxycycline and cefazolin at millimolar concentrations. LL-37 was surprisingly more effective in killing the clinical strain than in killing an ATCC strain ofS. aureus. Moreover, LL-37 was superior to conventional antibiotics in eliminating intracellularS. aureus. The kinetic studies further revealed that LL-37 was fast in eliminating both extra- and intracellularS. aureus. Therefore, LL-37 was shown to be very potent and prompt in eliminating both extra- and intracellularS. aureusand was more effective in killing extra- and intracellularS. aureusthan commonly used conventional antibiotics. LL-37 could potentially be used to treat chronic and recurrent infections due to its effectiveness in eliminating not only extracellular but also intracellular pathogens.