title: Meningococcal resistance to antimicrobial peptides is mediated by bacterial adhesion and host cell RhoA and Cdc42 signalling.
abstract: Antimicrobial peptides (AMPs) constitute an essential part of the innate immune defence. Pathogenic bacteria have evolved numerous strategies to withstand AMP-mediated killing. The influence of host epithelia on bacterial AMP resistance is, however, still largely unknown. We found that adhesion to pharyngeal epithelial cells protected Neisseria meningitidis, a leading cause of meningitis and sepsis, from the human cathelicidin LL-37, the cationic model amphipathic peptide (MAP) and the peptaibol alamethicin, but not from polymyxin B. Adhesion to primary airway epithelia resulted in a similar increase in LL-37 resistance. The inhibition of selective host cell signalling mediated by RhoA and Cdc42 was found to abolish the adhesion-induced LL-37 resistance by a mechanism unrelated to the actin cytoskeleton. Moreover, N. meningitidis triggered the formation of cholesterol-rich membrane microdomains in pharyngeal epithelial cells, and host cell cholesterol proved to be essential for adhesion-induced resistance. Our data highlight the importance of Rho GTPase-dependent host cell signalling for meningococcal AMP resistance. These results indicate that N. meningitidis selectively exploits the epithelial microenvironment in order to protect itself from LL-37.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Miriam
authors.initials: M
authors.lastname: Geörg
authors.forename: Lisa
authors.initials: L
authors.lastname: Maudsdotter
authors.forename: Raquel
authors.initials: R
authors.lastname: Tavares
authors.forename: Ann-Beth
authors.initials: AB
authors.lastname: Jonsson
mesh_terms: D000408:Alamethicin / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001422:Bacterial Adhesion; D002478:Cells, Cultured; D024881:Drug Resistance, Bacterial; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D009345:Neisseria meningitidis / Q000187:drug effects* / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C066737:RHOA protein, human; D000408:Alamethicin; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D054804:Cathelicidins