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
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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: November 02, 2022
Accepted:
October 28,
2022
Identification
Copyright
© 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
