| cathelicidin | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | cathelicidins | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | GeneCards: ; OMA:- orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the CAMP gene. [1] The active form is LL-37. In humans, CAMP encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37. [2] [1]
The cathelicidin family includes 30 types of which LL-37 is the only cathelicidin in the human. [3] Cathelicidins are stored in the secretory granules of neutrophils and macrophages and can be released following activation by leukocytes. [4] Cathelicidin peptides are dual-natured molecules called amphiphiles: one end of the molecule is attracted to water and repelled by fats and proteins, and the other end is attracted to fat and proteins and repelled by water. Members of this family react to pathogens by disintegrating, damaging, or puncturing cell membranes.
Cathelicidins thus serve a critical role in mammalian innate immune defense against invasive bacterial infection. [5] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous. [5] Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain. [5]
Cathelicidin peptides have been isolated from many different species of mammals, including marsupials. [6] Cathelicidins are mostly found in neutrophils, monocytes, mast cells, dendritic cells and macrophages [7] after activation by bacteria, viruses, fungi, parasites or the hormone 1,25-D, which is the hormonally active form of vitamin D. [8] They have been found in some other cells, including epithelial cells and human keratinocytes. [9]
The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins. [10] The name cathelin itself is coined from cathepsin L inhibitor in 1989. [11]
The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active. [4]
Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. Therefore, LL-37 can inhibit the formation of bacterial biofilms. [12]
LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process. [13] All these mechanisms together play an essential role in tissue homeostasis and regenerative processes. Moreover, it has an agonistic effect on various pleiotropic receptors, for example, formyl peptide receptor like-1 (FPRL-1), [14] purinergic receptor P2X7, epidermal growth factor receptor (EGFR). [15]
Furthermore, it induces angiogenesis [16] and regulates apoptosis. [17]
Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures. [18] Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures. [5]
In 1995, Gudmundsson et al. assumed that the active antimicrobial peptide is formed of a 39-residue C-terminal domain (termed FALL-39). However, only a year later stated that the matured AMP, now called LL-37, is in reality two amino acids shorter than FALL-39. [19] [20]
The cathelicidin family shares primary sequence homology with the cystatin [21] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.
Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, horses and wallabies. [22] Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial. [23] About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans. [4] Currently identified cathelicidin peptides include the following: [5]
Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea. [28] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs. [29]
Lower plasma levels of human cathelicidin antimicrobial protein (hCAP18) appear to significantly increase the risk of death from infection in dialysis patients. [30] The production of cathelicidin is up-regulated by vitamin D. [31] [32]
SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions. [33] In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms. [34]
LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate dendritic cells (a type of antigen presenting cell) which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation. [35] LL-37 has also been found to be a common auto-antigen in psoriasis; T-cells specific to LL-37 were found in the blood and skin in two thirds of patients with moderate to severe psoriasis. [35]
LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. An imbalance between LL-37 and Ab may be a factor affecting AD-associated fibrils and plaques. Chronic, oral Porphyromonas gingivalis , and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia. [36] [37]
Research into the AMP family—particularly in regards to their mechanism of action—has been ongoing for nearly 20 years. Despite sustained interest, treatments derived or utilizing AMPs have not been widely adopted for clinical use for several reasons. [38] One, drug candidates from AMPs have a narrow window of bioavailability, because peptides are quickly broken down by proteases. Two, peptide drugs are more expensive than small molecule drugs to produce, which is problematic since peptide drugs must be given in large doses to counter rapid enzymatic breakdown. These qualities also limit routes of administration, typically to injection, infusion, or slow release therapy. [39]
Peptoids, or poly-N-substituted glycines, are a class of biochemicals known as biomimetics that replicate the behavior of biological molecules. Peptidomimetics are recognizable by side chains that are appended to the nitrogen atom of the peptide backbone, rather than to the α-carbons.
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.
Proteinase 3, also known as PRTN3, is an enzyme that in humans is encoded by the PRTN3 gene.
Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.
Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.
C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.
N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.
N-Formylmethionyl-leucyl-phenylalanine is an N-formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic factor and is also a macrophage activator.
Serum amyloid A1 (SAA1) is a protein that in humans is encoded by the SAA1 gene. SAA1 is a major acute-phase protein mainly produced by hepatocytes in response to infection, tissue injury and malignancy. When released into blood circulation, SAA1 is present as an apolipoprotein associated with high-density lipoprotein (HDL). SAA1 is a major precursor of amyloid A (AA), the deposit of which leads to inflammatory amyloidosis.
Beta-defensin 2 (BD-2) also known as skin-antimicrobial peptide 1 (SAP1) is a peptide that in humans is encoded by the DEFB4 gene.
N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.
Defensin, alpha 1 also known as human alpha defensin 1, human neutrophil peptide 1 (HNP-1) or neutrophil defensin 1 is a human protein that is encoded by the DEFA1 gene. Human alpha defensin 1 belongs to the alpha defensin family of antimicrobial peptides.
Beta-defensin 1 is a protein that in humans is encoded by the DEFB1 gene.
Azurocidin also known as cationic antimicrobial protein CAP37 or heparin-binding protein (HBP) is a protein that in humans is encoded by the AZU1 gene.
Beta-defensin 103 is a protein that in humans is encoded by the DEFB103A gene.
Histone H2B type F-S is a protein that in humans is encoded by the H2BC12L gene. It's a histone H2B isoform.
Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.
Richard L. Gallo is an American dermatologist who is a Distinguished Professor and founding Chairman of Dermatology at the University of California, San Diego. His research accomplishments as a physician-scientist include discovery of antimicrobial peptides in mammalian skin, establishing new links between innate immunity and skin diseases such as atopic dermatitis and rosacea, and defining the functions of the skin microbiome in host immune defense.
Virtual colony count (VCC) is a kinetic, 96-well microbiological assay originally developed to measure the activity of defensins. It has since been applied to other antimicrobial peptides including LL-37. It utilizes a method of enumerating bacteria called quantitative growth kinetics, which compares the time taken for a bacterial batch culture to reach a threshold optical density with that of a series of calibration curves. The name VCC has also been used to describe the application of quantitative growth kinetics to enumerate bacteria in cell culture infection models. Antimicrobial susceptibility testing (AST) can be done on 96-well plates by diluting the antimicrobial agent at varying concentrations in broth inoculated with bacteria and measuring the minimum inhibitory concentration that results in no growth. However, these methods cannot be used to study some membrane-active antimicrobial peptides, which are inhibited by the broth itself. The virtual colony count procedure takes advantage of this fact by first exposing bacterial cells to the active antimicrobial agent in a low-salt buffer for two hours, then simultaneously inhibiting antimicrobial activity and inducing exponential growth by adding broth. The growth kinetics of surviving cells can then be monitored using a temperature-controlled plate reader. The time taken for each growth curve to reach a threshold change in optical density is then converted into virtual survival values, which serve as a measure of antimicrobial activity.
Formyl peptide receptor 1 is a cell surface receptor protein that in humans is encoded by the formyl peptide receptor 1 (FPR1) gene. This gene encodes a G protein-coupled receptor cell surface protein that binds and is activated by N-Formylmethionine-containing oligopeptides, particularly N-Formylmethionine-leucyl-phenylalanine (FMLP). FPR1 is prominently expressed by mammalian phagocytic and blood leukocyte cells where it functions to mediate these cells' responses to the N-formylmethionine-containing oligopeptides which are released by invading microorganisms and injured tissues. FPR1 directs these cells to sites of invading pathogens or disrupted tissues and then stimulates these cells to kill the pathogens or to remove tissue debris; as such, it is an important component of the innate immune system that operates in host defense and damage control.