L-Rhamnosylation of Listeria monocytogenes Wall Teichoic Acids Promotes Resistance to Antimicrobial Peptides by Delaying Interaction with the Membrane

• Autor(a) principal: Carvalho, F
• Data de Publicação: 2015
• Outros Autores: Atilano, ML, Pombinho, R, Covas, G, Gallo, RL, Filipe, SR, Sousa, S, Cabanes, D
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10216/114513
• topic: Animals; Anti-Infective Agents/pharmacology; Antimicrobial Cationic Peptides/pharmacology; Cell Membrane/metabolism; Cell Wall/metabolism; Cells, Cultured; Drug Resistance, Bacterial/drug effects; Glycosylation; Humans; Listeria monocytogenes/physiology; Listeriosis/drug therapy; Listeriosis/microbiology; Macrophages/drug effects; Macrophages/microbiology; Mice; Mice, Inbred BALB C; Rhamnose/chemistry; Teichoic Acids/pharmacology; Virulence

Listeria monocytogenes is an opportunistic Gram-positive bacterial pathogen responsible for listeriosis, a human foodborne disease. Its cell wall is densely decorated with wall teichoic acids (WTAs), a class of anionic glycopolymers that play key roles in bacterial physiology, including protection against the activity of antimicrobial peptides (AMPs). In other Grampositive pathogens, WTA modification by amine-containing groups such as D-alanine was largely correlated with resistance to AMPs. However, in L. monocytogenes, where WTA modification is achieved solely via glycosylation, WTA-associated mechanisms of AMP resistance were unknown. Here, we show that the L-rhamnosylation of L. monocytogenes WTAs relies not only on the rmlACBD locus, which encodes the biosynthetic pathway for Lrhamnose, but also on rmlT encoding a putative rhamnosyltransferase. We demonstrate that this WTA tailoring mechanism promotes resistance to AMPs, unveiling a novel link between WTA glycosylation and bacterial resistance to host defense peptides. Using in vitro binding assays, fluorescence-based techniques and electron microscopy, we show that the presence of L-rhamnosylated WTAs at the surface of L. monocytogenes delays the crossing of the cell wall by AMPs and postpones their contact with the listerial membrane. We propose that WTA L-rhamnosylation promotes L. monocytogenes survival by decreasing the cell wall permeability to AMPs, thus hindering their access and detrimental interaction with the plasma membrane. Strikingly, we reveal a key contribution of WTA L-rhamnosylation for L. monocytogenes virulence in a mouse model of infection.