Cathelicidin Host Defence Peptide Augments Clearance of Pulmonary Pseudomonas aeruginosa Infection by Its Influence on Neutrophil Function In Vivo (original) (raw)
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Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide
Infection and immunity, 1999
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 int...
Cathelicidins: Immunomodulatory Antimicrobials
Vaccines
Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions. These effector molecules of the innate immune system of many vertebrates are diverse in their amino acid sequence but share physicochemical characteristics like positive charge and amphipathicity. Besides being antimicrobial, cathelicidins have a wide variety in immunomodulatory functions, both boosting and inhibiting inflammation, directing chemotaxis, and effecting cell differentiation, primarily towards type 1 immune responses. In this review, we will examine the biology and various functions of cathelicidins, focusing on putting in vitro results in the context of in vivo situations. The pro-inflammatory and anti-inflammatory functions are highlighted, as well both direct and indirect effects on chemotaxis and cell differentiation. Additionally, we will discuss the potential and limitations of using cathelicidins as immunomodulatory or antimicrobial drugs.
Cathelicidins: family of antimicrobial peptides. A review
Molecular Biology Reports, 2012
Cathelicidins are small, cationic, antimicrobial peptides found in humans and other species, including farm animals (cattle, horses, pigs, sheep, goats, chickens, rabbits and in some species of fish). These proteolytically activated peptides are part of the innate immune system of many vertebrates. These peptides show a broad spectrum of antimicrobial activity against bacteria, enveloped viruses and fungi. Apart from exerting direct antimicrobial effects, cathelicidins can also trigger specific defense responses in the host. Their roles in various pathophysiological conditions have been studied in mice and humans, but there are limited information about their expression sites and activities in livestock. The aim of the present review is to summarize current information about these antimicrobial peptides in farm animals, highlighting peptide expression sites, activities, and future applications for human and veterinary medicine.
Cathelicidins PMAP-36, LL-37 and CATH-2 are similar peptides with different modes of action
Scientific Reports
Host defense peptides (HDPs) play a pivotal role in innate immunity and have, in addition to antimicrobial activity, also important immunomodulatory functions. Bacteria are less likely to develop resistance against HDPs because these peptides target and kill bacteria in multiple ways, as well as modulate the immune system. Therefore, HDPs, and derivatives thereof, are promising alternatives to traditional antibiotics. Hardly anything is known about the immunomodulatory functions of porcine cathelicidin PMAP-36. In this study, we aimed to determine both antibacterial and immunomodulatory activities of PMAP-36 comparing the properties of PMAP-36 analogs with two well-studied peptides, human LL-37 and chicken CATH-2. Transmission electron microscopy revealed different killing mechanisms of E. coli for PMAP-36, CATH-2 and LL-37. LL-37 binds LPS very weakly in contrast to PMAP-36, but it inhibits LPS activation of macrophages the strongest. The first 11 amino acids of the N-terminal side of PMAP-36 are dispensable for E. coli killing, LPS-neutralization and binding. Deletion of four additional amino acids resulted in a strong decrease in activity. The activity of full length PMAP-36 was not affected by monomerization, whereas the shorter analogs require dimerization for proper immunomodulatory activity but not for their antibacterial activity. Cathelicidins constitute a family of host defense peptides (HDPs) and play an important role during the innate immune response 1. They consist of a highly conserved N-terminal region, containing a signal peptide and a cathelin domain, while the C-terminal region represents the highly variable domain of the active peptide 2-4. Although the sequences of cathelicidins are highly variable, almost all cathelicidins show, in simple media, direct antimicrobial activity against many different bacteria 3,5-7 , viruses 8-10 , fungi 11 , and parasites 12,13. Besides their direct antimicrobial activities, cathelicidins can also modulate the immune response. These peptides can induce chemotaxis directly or indirectly by inducing chemokine release 3,14,15. In addition, cathelicidins have been shown to be involved in phagocytosis 3,16-18 , neutralization of LPS or LTA during TLR stimulation 3,15,19,20 or enhancement of DNA uptake and subsequent TLR-9 activation 3,5,21,22 and they can skew macrophage differentiation towards a pro-inflammatory phenotype 23. Bacteria are less likely to develop resistance against HDPs because they do not only target and kill bacteria in multiple ways but also modulate the immune system. This dual function makes HDPs promising alternatives to antibiotics. In humans only one cathelicidin has been identified, LL-37 2 , while in chicken four cathelicidins have been identified, CATH-B1 and CATH-1-3 24. The pig has an even larger arsenal of 11 cathelicidins: protegrin-1-5, prophenin-1-2, and pig myeloid antibacterial peptide (PMAP)-23,-36, and-37 4. Human LL-37 is a 37 amino acid cationic (6+) peptide and has been widely studied. LL-37 penetrates the bacterial membrane and forms pores in the membrane. LL-37 adopts an α-helical structure 25 , which resembles the structure of PMAP-36. In addition, many different immunomodulatory functions have been described for LL-37 26-28. Chicken CATH-2 is a 26 amino acid cationic (11+) arginine-lysine-rich peptide, consisting of two α-helical regions with a proline induced hinge region 29. CATH-2 displays strong antimicrobial activities against many different pathogens, e.g. Gram-positive and Gram-negative bacteria 29-32 and fungi 32,33. In addition, CATH-2 has been shown to have immunomodulatory capacities 29,30,34 .
Scientific reports, 2017
Cathelicidins are short cationic peptides initially described as antimicrobial peptides, which can also modulate the immune system. Because most findings have been described in the context of human LL-37 or murine CRAMP, or have been investigated under varying conditions, it is unclear which functions are cathelicidin specific and which functions are general cathelicidin properties. This study compares 12 cathelicidins from 6 species under standardized conditions to better understand the conservation of cathelicidin functions. Most tested cathelicidins had strong antimicrobial activity against E. coli and/or MRSA. Interestingly, while more physiological culture conditions limit the antimicrobial activity of almost all cathelicidins against E. coli, activity against MRSA is enhanced. Seven out of 12 cathelicidins were able to neutralize LPS and another 7 cathelicidins were able to neutralize LTA; however, there was no correlation found with LPS neutralization. In contrast, only 4 cat...
Activity of Antimicrobial Peptide; Cathelicidin, on Bacterial Infection
The Open Biochemistry Journal
Antimicrobial peptide is an effector molecule from the natural immune system which plays a central role in defense as an antimicrobial. Cathelicidin is one of the antimicrobial peptides. Human only has one cathelicidin antimicrobial peptide called LL-37 or hCAP18. The detailed mechanism on CAMP (Cathelicidin Antimicrobial Peptide) gene regulation is still unknown, however, cathelicidin is found to have upregulation when there is bacterial infection. The most effective expression inducer of CAMP gene is 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3), which is the active form of vitamin D. Vitamin D mediates cathelicidin synthesis through the expression of Vitamin D Receptor (VDR), then the interaction activates CAMP gene to express cathelicidin. The work mechanisms of cathelicidin against bacterial infection include damaging the bacterial cell membrane, inducing autophagy process of macrophage cell, neutralizing LPS produced by bacteria, and chemotactic activities of PMNs, monocytes and lym...
mBio, 2016
The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria. Cathelicidins are antimicrobial peptides that can also increase inflamm...
Antimicrobial Agents and Chemotherapy, 2001
, three novel alpha-helical peptides derived from SMAP29 and termed ovispirins (OV-1, OV-2, and OV-3), and two derivatives of CAP18 were tested by broth microdilution assays. Their MICs were determined for multiply antibiotic-resistant Pseudomonas aeruginosa (n ؍ 24), Burkholderia cepacia (n ؍ 5), Achromobacter xylosoxidans (n ؍ 5), and Stenotrophomonas maltophilia (n ؍ 5) strains isolated from CF patients. SMAP29 was most active and inhibited mucoid and nonmucoid P. aeruginosa strains (MIC, 0.06 to 8 g/ml). OV-1, OV-2, and OV-3 were nearly as active (MIC, 0.03 to 16 g/ml), but CAP18 (MIC, 1.0 to 32 g/ml), CAP18-18 (MIC, 1.0 to >32 g/ml), and CAP18-22 (MIC, 0.5 to 32 g/ml) had variable activities. LL37, mCRAMP, and rCRAMP were least active against the clinical isolates studied (MIC, 1.0 to >32 g/ml). Peptides had modest activities against S. maltophilia and A. xylosoxidans (MIC range, 1.0 to > 32 g/ml), but none inhibited B. cepacia. However, CF sputum inhibited the activity of SMAP29 substantially. The effects of peptides on bacterial cell membranes and eukaryotic cells were examined by scanning electron microscopy and by measuring transepithelial cell resistance, respectively. SMAP29 caused the appearance of bacterial membrane blebs within 1 min, killed P. aeruginosa within 1 h, and caused a dose-dependent, reversible decrease in transepithelial resistance within 5 h. The tested cathelicidin-derived peptides represent a novel class of antimicrobial agents and warrant further development as prophylactic or therapeutic agents for CF lung disease.
The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2016
The human cathelicidin hCAP18/LL-37 has become a paradigm for the pleiotropic roles of peptides in host defence. It has a remarkably wide functional repertoire that includes direct antimicrobial activities against various types of microorganisms, the role of 'alarmin' that helps to orchestrate the immune response to infection, the capacity to locally modulate inflammation both enhancing it to aid in combating infection and limiting it to prevent damage to infected tissues, the promotion of angiogenesis and wound healing, and possibly also the elimination of abnormal cells. LL-37 manages to carry out all its reported activities with a small and simple, amphipathic, helical structure. In this review we consider how different aspects of its primary and secondary structures, as well as its marked tendency to form oligomers under physiological solution conditions and then bind to molecular surfaces as such, explain some of its cytotoxic and immunomodulatory effects. We consider its modes of interaction with bacterial membranes and capacity to act as a pore-forming toxin directed by our organism against bacterial cells, contrasting this with the mode of action of related peptides from other species. We also consider its different membrane-dependent effects on our own cells, which underlie many of its other activities in host defence. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.