title: Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection.
abstract: Regulation of neutrophil activity is critical for immune evasion among extracellular pathogens, yet the mechanisms by which many bacteria disrupt phagocyte function remain unclear. Here, we have shown that the respiratory pathogen Streptococcus pneumoniae disables neutrophils by exploiting molecular mimicry to degrade platelet-activating factor (PAF), a host-derived inflammatory phospholipid. Using mass spectrometry and murine upper airway infection models, we demonstrated that phosphorylcholine (ChoP) moieties that are shared by PAF and the bacterial cell wall allow S. pneumoniae to leverage a ChoP-remodeling enzyme (Pce) to remove PAF from the airway. S. pneumoniae-mediated PAF deprivation impaired viability, activation, and bactericidal capacity among responding neutrophils. In the absence of Pce, neutrophils rapidly cleared S. pneumoniae from the airway and impeded invasive disease and transmission between mice. Abrogation of PAF signaling rendered Pce dispensable for S. pneumoniae persistence, reinforcing that this enzyme deprives neutrophils of essential PAF-mediated stimulation. Accordingly, exogenous activation of neutrophils overwhelmed Pce-mediated phagocyte disruption. Haemophilus influenzae also uses an enzyme, GlpQ, to hydrolyze ChoP and subvert PAF function, suggesting that mimicry-driven immune evasion is a common paradigm among respiratory pathogens. These results identify a mechanism by which shared molecular structures enable microbial enzymes to subvert host lipid signaling, suppress inflammation, and ensure bacterial persistence at the mucosa.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Hergott
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Roche
authors.forename: Nikhil A
authors.initials: NA
authors.lastname: Naidu
authors.forename: Clementina
authors.initials: C
authors.lastname: Mesaros
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002353:Carrier State / Q000382:microbiology; D002473:Cell Wall / Q000737:chemistry* / Q000276:immunology; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000502:physiology*; D007113:Immunity, Innate; D007072:Immunoglobulin D / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009296:Nasal Cavity / Q000276:immunology / Q000382:microbiology*; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010587:Phagocytosis; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology*; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000502:physiology; D013045:Species Specificity; D013296:Streptococcus pneumoniae / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D007072:Immunoglobulin D; D008074:Lipoproteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C526540:choline-binding protein E, Streptococcus pneumoniae; C039351:platelet activating factor receptor; D010767:Phosphorylcholine; D009240:N-Formylmethionine Leucyl-Phenylalanine; C067989:glpQ protein, Haemophilus influenzae