Brameshuber, M. (Mario)

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    The antimicrobial peptide cathelicidin and polymyxin B neutralize endotoxins by a multifactorial mechanism including not only direct LPS-interaction but also targeting of host cell membrane domains
    (PNAS, 2021) Brandenburg, K. (Klaus); Kopp, F. (Franziska); Kaconis, Y. (Yani); Donoghue, A. (Annemarie); Gutsmann, T. (Thomas); Nehls, C. (Christian); Koistinen, M. (Max); Sánchez-Gómez, S. (Susana); Wernecke, J. (Julia); Sevcsik, E. (Eva); Andrä, J. (Jörg); Martinez-de-Tejada, G. (Guillermo); Schütz, G.J. (Gerhard J.); Paulowski, L. (Laura); Brameshuber, M. (Mario); Lohner, K. (Karl); Keese, S. (Susanne); Garidel, P. (Patrick); Schromm, A.B. (Andra B.)
    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.