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.
View: Text | PDF
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

×

Figure 4

Pce is dispensable for pneumococcal persistence in the absence of infiltrating neutrophils or intact PAF signaling in the upper airway.

Options: View larger image (or click on image) Download as PowerPoint
Pce is dispensable for pneumococcal persistence in the absence of infilt...
(A) Confirmation of neutrophil depletion. Mice were treated with neutrophil-depleting antibody (α-Ly6G, clone 1A8) or IgG2a isotype control (250 μg, i.p.) on days –1, +1, and +4 p.i. with PBS (white), WT (black), or Δpce (gray) P1121 pneumococci (n = 3–4 mice per condition). On day 7 p.i., depletion was confirmed by flow cytometric analysis of whole blood and nasal lavage. (B) Enumeration of WT (black) or Δpce (gray) pneumococcal CFU obtained from nasal lavages on day 7 p.i. and after treatment of mice (n = 5–11 mice per group) with neutrophil-depleting α-Ly6G or IgG2a isotype control antibodies. (C) Enumeration of bacterial CFU on day 7 p.i. and after daily i.n. treatment with 0.1 or 1 μg PAFR antagonist PCA-4248 (or 1% DMSO vehicle), from days +1 to +6 p.i. (n = 5–12). The experiment was repeated with neutrophil depletion as described in A. (D) WT and Δpce bacterial loads were enumerated in lavages obtained from Ptafr–/– mice and their littermate controls on day 7 p.i. (n = 5–11). *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA with Newman-Keuls post test.