Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes

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 le-

thality 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 biophys-

ical basis, we demonstrate modifications of the structure of cholesterol-rich membrane domains and the association of glycosyl- phosphatidylinositol (GPI)-anchored proteins. Our discovery of a

host cell-directed mechanism of immune control contributes an im- portant aspect in the development and therapeutic use of AMPs.