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Toxoplasma gondii infection triggers ongoing inflammation mediated by increased intracellular Cl concentration in airway epithelium

Published:November 02, 2022DOI:https://doi.org/10.1016/j.jinf.2022.10.037

      Highlights

      • T. gondii secretes cysteine proteases to degrade CFTR expressed in airway epithelial cells.
      • Degradation of CFTR triggers airway inflammation via Cl-SGK1-NF-κB signaling.
      • T. gondii up-regulated PDE4 to evoke a sustained elevation in [Cl]i and ongoing inflammation.
      • Allicin exerted anti-Toxoplasma properties by reconstructing intracellular Cl homeostasis.

      Summary

      Toxoplasma gondii is a widespread parasitic protozoan causing toxoplasmosis including pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii, the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl concentration ([Cl]i) was consequently elevated, leading to activation of nuclear factor-κB (NF-κB) signaling via serum/glucocorticoid regulated kinase 1. Furthermore, the heightened [Cl]i and activated NF-κB signaling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP level through NF-κB-mediated up-regulation of phosphodiesterase 4. Conversely, the sulfur-containing compound allicin conferred anti-inflammatory effects on pulmonary toxoplasmosis by decreasing [Cl]i via activation of CFTR. These results suggest that the intracellular Cl dynamically modulated by T. gondii mediates sustained airway inflammation, which provides a potential therapeutic target against pulmonary toxoplasmosis.

      Graphical abstract

      Keywords

      Abbreviations:

      [Cl−]i (intracellular Cl− concentration), ANO1 (anoctamin 1), ASL (airway surface liquid), CaCC (Ca2+-activated Cl− channel), CFTR (cystic fibrosis transmembrane conductance regulator), CP (cysteine protease), eGFP (enhanced green fluorescent protein), hAECs (human airway epithelial cells), HE (hematoxylin and eosin), IκB (inhibitor of NF-κB), IFN-γ (interferon-γ), IL (interleukin), ISC (short-circuit current), KO (knockout), mAECs (mouse airway epithelial cells), MOI (multiplicity of infection), NF-κB (nuclear factor-κB), PDE4 (phosphodiesterase 4), SD (standard deviation), SGK1 (serum/glucocorticoid regulated kinase 1), Sup (supernatant), Th (T helper), TLR (Toll-like receptor), TNF-α (tumor necrosis factor-α)
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