Detalle Publicación

ARTÍCULO
Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes
Autores: Schromm, A. B. (Autor de correspondencia); Paulowski, L.; Kaconis, Y.; Kopp, F.; Koistinen, M.; Donoghue, A.; Keese, S.; Nehls, C.; Wernecke, J.; Garidel, P.; Sevcsik, E.; Lohner, K.; Sánchez Gómez, Susana; Martínez de Tejada de Garaizábal, Guillermo; Brandenburg, K.; Brameshuber, M.; Schuetz, G. J.; Andrae, J.; Gutsmann, T.
Título de la revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN: 0027-8424
Volumen: 118
Número: 27
Páginas: e2101721118
Fecha de publicación: 2021
Lugar: WOS
Resumen:
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 peptidemediated 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.