title: NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA.
abstract: Strengthening the host immune system to fully exploit its potential as antimicrobial defense is vital in countering antibiotic resistance. Chemical compounds released during bidirectional host-pathogen cross-talk, which follows a sensing-response paradigm, can serve as protective mediators. A potent, diffusible messenger is hydrogen peroxide (H2O2), but its consequences on extracellular pathogens are unknown. Here we show that H2O2, released by the host on pathogen contact, subverts the tyrosine signaling network of a number of bacteria accustomed to low-oxygen environments. This defense mechanism uses heme-containing bacterial enzymes with peroxidase-like activity to facilitate phosphotyrosine (p-Tyr) oxidation. An intrabacterial reaction converts p-Tyr to protein-bound dopa (PB-DOPA) via a tyrosinyl radical intermediate, thereby altering antioxidant defense and inactivating enzymes involved in polysaccharide biosynthesis and metabolism. Disruption of bacterial signaling by DOPA modification reveals an infection containment strategy that weakens bacterial fitness and could be a blueprint for antivirulence approaches.
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland;
authors: Luis A
authors: LA
authors: Alvarez
authors: Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland;
authors: Lidija
authors: L
authors: Kovačič
authors: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland;
authors: Javier
authors: J
authors: Rodríguez
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland;
authors: Jan-Hendrik
authors: JH
authors: Gosemann
authors: Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland;
authors: Malgorzata
authors: M
authors: Kubica
authors: Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland;
authors: Gratiela G
authors: GG
authors: Pircalabioru
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland;
authors: Florian
authors: F
authors: Friedmacher
authors: Faculty of Veterinary Medicine, Banat University of Agricultural Sciences and Veterinary Medicine "King Michael I of Romania", 300645 Timisoara, Romania;
authors: Ada
authors: A
authors: Cean
authors: Faculty of Veterinary Medicine, Banat University of Agricultural Sciences and Veterinary Medicine "King Michael I of Romania", 300645 Timisoara, Romania;
authors: Alina
authors: A
authors: Ghişe
authors: Faculty of Veterinary Medicine, Banat University of Agricultural Sciences and Veterinary Medicine "King Michael I of Romania", 300645 Timisoara, Romania;
authors: Mihai B
authors: MB
authors: Sărăndan
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland;
authors: Prem
authors: P
authors: Puri
authors: School of Chemistry, University of Edinburgh, Edinburgh EH9 3F, United Kingdom;
authors: Simon
authors: S
authors: Daff
authors: Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors: Erika
authors: E
authors: Plettner
authors: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland;
authors: Alex
authors: A
authors: von Kriegsheim
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland; Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland; billy.bourke@ucd.ie ulla.knaus@ucd.ie.
authors: Billy
authors: B
authors: Bourke
authors: National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland; Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland; billy.bourke@ucd.ie ulla.knaus@ucd.ie.
authors: Ulla G
authors: UG
authors: Knaus
mesh_terms: D016123:Campylobacter jejuni / Q000378:metabolism / Q000472:pathogenicity; D002460:Cell Line; D004295:Dihydroxyphenylalanine / Q000737:chemistry / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000276:immunology; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007107:Immune System / Q000378:metabolism / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000378:metabolism / Q000472:pathogenicity; D008089:Listeria monocytogenes / Q000378:metabolism / Q000472:pathogenicity; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019779:Salmonella enterica / Q000378:metabolism / Q000472:pathogenicity; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019000:Phosphotyrosine; D014443:Tyrosine; D006418:Heme; D004295:Dihydroxyphenylalanine; D006861:Hydrogen Peroxide; D009195:Peroxidase; D019255:NADPH Oxidases; D010100:Oxygen
keywords: DOPA; NADPH oxidase; bacterial tyrosine phosphorylation; mucosal immunity; reactive oxygen species (ROS)