Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection
Christopher B. Hergott, … , Ian A. Blair, Jeffrey N. Weiser
Christopher B. Hergott, … , Ian A. Blair, Jeffrey N. Weiser
Published August 31, 2015
Citation Information: J Clin Invest. 2015;125(10):3878-3890. https://doi.org/10.1172/JCI81888.
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Research Article Pulmonology

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

Christopher B. Hergott, Aoife M. Roche, Nikhil A. Naidu, Clementina Mesaros, Ian A. Blair, Jeffrey N. Weiser

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Figure 7

H. influenzae GlpQ hydrolyzes ChoP and contributes to evasion of PAF-mediated neutrophil defense of the airway.

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H. influenzae GlpQ hydrolyzes ChoP and contributes to evasion of PAF-me...
(A) Diagram of pNPPC. Black arrow denotes the site of hydrolysis by S. pneumoniae Pce; white arrow indicates hydrolysis by H. influenzae GlpQ. (B) p-nitrophenol liberation after incubating pNPPC with WT (black) or mutant (gray) S. pneumoniae (Sp) or H. influenzae (Hi) (n = 5). (C) Survival of WT (black) or ΔglpQ (gray) H. influenzae during infection of the murine upper airway (n = 5–8 mice per group, LOD = 4). (D) Quantification of neutrophils obtained from mice inoculated with WT or ΔglpQ bacteria (n = 4). (E) CD11b and CD64 relative MFI on neutrophils elicited by WT or ΔglpQ bacteria, day 2 p.i. (n = 4). (F) Enumeration of day-2 WT or ΔglpQ H. influenzae CFU after treatment with α-Ly6G antibody or IgG2a isotype control (n = 5, LOD = 4). (G) WT and ΔglpQ bacterial loads from Ptafr–/–mice, littermate controls, or neutropenic Ptafr–/– mice on day 2 p.i. (n = 3–9, LOD = 10). (H) Bacterial killing assay of WT H. influenzae by 1,000:1 murine neutrophils pretreated with increasing concentrations of conditioned PAF media; PAF was preincubated with heat-killed WT (black) or ΔglpQ (white) bacteria before mixing with neutrophils for killing assays. Average values represent 3 biological replicates. Top dotted line: 100% bacterial survival; bottom dotted line: average survival in the absence of PAF. Statistical significance was assessed by Student’s t test for pairwise comparisons (B and H); 1-way ANOVA with Newman-Keuls post test for multigroup comparisons (C, D, F, and G); and 1-sample Student’s t test relative to null = 1 for relative MFI measurements (E). *P < 0.05, **P < 0.01, ***P < 0.001.