Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes.
Proc Natl Acad Sci U S A
; 118(27)2021 07 06.
Article
in En
| MEDLINE
| ID: mdl-34183393
ABSTRACT
Antimicrobial peptides (AMPs) contribute to an effective protection against infections. The antibacterial function of AMPs depends on their interactions with microbial membranes and lipids, such as lipopolysaccharide (LPS; endotoxin). Hyperinflammation induced by endotoxin is a key factor in bacterial sepsis and many other human diseases. Here, we provide a comprehensive profile of peptide-mediated LPS neutralization by systematic analysis of the effects of a set of AMPs and the peptide antibiotic polymyxin B (PMB) on the physicochemistry of endotoxin, macrophage activation, and lethality in mice. Mechanistic studies revealed that the host defense peptide LL-32 and PMB each reduce LPS-mediated activation also via a direct interaction of the peptides with the host cell. As a biophysical basis, we demonstrate modifications of the structure of cholesterol-rich membrane domains and the association of glycosylphosphatidylinositol (GPI)-anchored proteins. Our discovery of a host cell-directed mechanism of immune control contributes an important aspect in the development and therapeutic use of AMPs.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polymyxin B
/
Neutralization Tests
/
Cell Membrane
/
Lipopolysaccharides
/
Cathelicidins
/
Host-Pathogen Interactions
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2021
Type:
Article