Abstract
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.
Highlights
Cathelicidins constitute a family of host defense peptides (HDPs) and play an important role during the innate immune response[1]
The antibacterial and immunomodulatory properties of pig myeloid antibacterial peptide (PMAP)-36 were studied in a systematic manner
LL-37 adopts to an α-helix of almost the entire peptide, while CATH-2 is characterized by two short α-helical fragments that are connected by a proline-induced hinge region
Summary
Cathelicidins constitute a family of host defense peptides (HDPs) and play an important role during the innate immune response[1]. 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]. Porcine cathelicidin PMAP-36 was first described in 1994 as a 36-amino acids long, highly cationic (13+), amphipathic, α-helical antimicrobial peptide with a proline-induced hinge region. The peptide strongly enhances bacterial DNA (TLR-9) stimulation of porcine dendritic cells (pDC), resulting in an increased IFN-α response[21]. This effect appears to be cell or species specific, since no enhanced activation of murine macrophages by DNA stimulation was found[3]. Prevention of dimerization slightly enhanced the antimicrobial activity and reduced the cytotoxic effects
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