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 1

Pce-deficient pneumococci exhibit impaired persistence in the upper airway and elicit the recruitment of more activated, viable, and durable neutrophils to the nasal lumen.

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Pce-deficient pneumococci exhibit impaired persistence in the upper airw...
(A) Bacterial clearance in mice inoculated with WT pneumococci, strain P1121 (Type 23F), with (white circles) or without (black circles) systemic neutrophil depletion (n = 4–5 mice per condition, limit of detection [LOD] = 2). (B) Survival of WT P1121 (black) or P1121Δpce (gray) pneumococci in the murine upper airway (n = 4–14). (C) Day-7 survival of P1121Δpce mutant generated by in-frame, unmarked deletion (Δpce) and with genetic correction (Δpce::pce) (n = 5). (D) Day 7 survival of WT and Δpce pneumococci on a type 4 (T4, TIGR4) pneumococcal genetic background (n = 5). (E) Quantification of neutrophils (CD45+CD11b+Ly6G+) obtained from the upper airway lumen by nasal lavage before (n = 3) and after (n = 4–11) inoculation with WT (black) or Δpce (gray) pneumococci. (F) Flow cytometric characterization of luminal neutrophils elicited by infection with WT or Δpce pneumococci on day 4 p.i. (n = 6–8). Note that not all axes are continuous, and gaps in axes represent gaps in time. Dotted lines represent the LOD. Statistical significance was assessed by 1-way ANOVA with Newman-Keuls post test for comparisons of more than 2 conditions (A, B, and E), Student’s t test for 2-group comparisons (C and D), and 1-sample Student’s t test relative to null = 1 for relative MFI measurements (F). *P < 0.05, ***P < 0.001.