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 3

Pce prevents accumulation of PAF in the lumen of the upper respiratory tract, and the absence of Pce stimulates transcription of genes important for PAF signaling.

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Pce prevents accumulation of PAF in the lumen of the upper respiratory t...
(A) Diagram of PAF with the ChoP moiety labeled (and site of Pce-mediated hydrolysis marked with a black arrow). Detection of PAF levels in the upper airway lumen by LC-ESI/MS (limit of quantification = 0.066 nM, dashed line), quantified from pooled nasal lavages obtained from 5 mice at 3 days p.i. with PBS (Mock, white), WT (black), or Δpce (gray) P1121 pneumococci. Averages reflect 3 independent biological replicates of 5 pooled mice each. Statistical significance was assessed by 1-way ANOVA with Newman-Keuls post test. For representative LC traces from lavage fluid of mock-, WT-, and Δpce-infected mice, the top row displays PAF detected at 8.6 minutes’ retention; the bottom row displays 2H4-PAF C16–spiked control samples. (B) qRT-PCR measurements of relative gene expression of the PAF synthetic enzyme Lpcat2, PAFR (Ptafr), and chemokines Cxcl1 and Cxcl2 from nasal lavages obtained 3 days p.i. from mice colonized with PBS, WT, or Δpce P1121 pneumococci (n = 6–10 mice per condition). All transcripts were normalized to GAPDH controls and are displayed relative to mice mock-infected with PBS (dotted lines). *P < 0.05 by Student’s t test.