Abstract
Cathelicidin genes homologous to the human CAMP gene, coding for the host defense peptide LL-37, have been sequenced and analyzed in 20 primate species, including Great Apes, hylobatidae, cercopithecidae, callithricidae, and cebidae. The region corresponding to the putative mature antimicrobial peptide is subject to a strong selective pressure for variation, with evidence for positive selection throughout the phylogenetic tree relating the peptides, which favors alterations in the charge while little affecting overall hydrophobicity or amphipathicity. Selected peptides were chemically synthesized and characterized, and two distinct types of behavior were observed. Macaque and leaf-eating monkey RL-37 peptides, like other helical antimicrobial peptides found in insect, frog, and mammalian species, were unstructured in bulk solution and had a potent, salt and medium independent antimicrobial activity in vitro, which may be the principal function also in vivo. Human LL-37 and the orangutan, hylobates, and callithrix homologues instead showed a salt-dependent structuring and likely aggregation in bulk solution that affected antimicrobial activity and its medium dependence. The two types of peptides differ also in their interaction with host cells. The evolution of these peptides has thus resulted in distinct mechanisms of action that affect the direct antimicrobial activity and may also modulate accessory antimicrobial functions due to interactions with host cells.
Highlights
Host defense peptides (HDPs),4 produced by epithelial and phagocytic cells, are an important component of innate immune
The only cathelicidin gene present in humans (CAMP) is expressed in inflammatory and epithelial cells, and its product contains a 30-residue signal region, a 103-residue polypeptide corresponding to the conserved cathelin-like proregion, and the 37-residue peptide LL-37 at the C terminus, which becomes antimicrobially active on release from the proregion by the action of proteinase 3 [10]
In line with the widening role of antimicrobial peptides as effector molecules of innate immunity, LL-37 was found to bind to formyl peptide receptor-like 1 (FPRL1), a G protein-coupled, 7-transmembrane cell receptor found on macrophages, neutrophils, and subsets of lymphocytes [13]
Summary
Circular dichroism studies indicate that these peptides are generally unstructured in bulk solution, and adopt a helical conformation only in contact with membrane-like environments, whereas most of the published evidence indicates that they act by disrupting the bacterial membrane [7,8,9] This type of cathelicidin HDP has been identified in rodents (rabbit rCAP-18, mouse and rat CRAMP, and guinea pig CAP-11), primates (human LL-37 and rhesus RL-37), bovids (bovine BMAP-27, -28, and -34, sheep SMAP-29 and -34, and goat MAP-28 and -34), horse (eCATH-1 to -3), and pig (PMAP-23, -36, and -37), and a putative member has recently been identified in dog [2]. We have investigated whether any of these variations could be due to a positive selective pressure, possibly derived from exposure to different biotas and/or pathogens
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