Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to Pneumocystis carinii ß-glucans.
Antimicrob Agents Chemother
; 68(2): e0081123, 2024 Feb 07.
Article
in En
| MEDLINE
| ID: mdl-38206037
ABSTRACT
Pneumocystis jirovecii, the fungus that causes Pneumocystis jirovecii pneumonia (PJP), is a leading cause of morbidity and mortality in immunocompromised individuals. We have previously shown that lung epithelial cells can bind Pneumocystis spp. ß-glucans via the EphA2 receptor, resulting in activation and release of proinflammatory cytokines. Herein, we show that in vivo Pneumocystis spp. ß-glucans activation of the inflammatory signaling cascade in macrophages can be pharmacodynamically inhibited with the EphA2 receptor small-molecule inhibitor ALW-II-41-27. In vitro, when ALW-II-41-27 is administrated via intraperitoneal to mice prior to the administration of highly proinflammatory Saccharomyces cerevisiae ß-glucans in the lung, a significant reduction in TNF-alpha release was noted in the ALW-II-41-27 pre-treated group. Taken together, our data suggest that targeting host lung macrophage activation via EphA2 receptor-fungal ß-glucans interactions with ALW-II-41-27 or other EphA2 receptor kinase targeting inhibitors might be an attractive and viable strategy to reduce detrimental lung inflammation associated with PJP.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pneumocystis
/
Pneumonia, Pneumocystis
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Benzamides
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Niacinamide
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Receptor, EphA2
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Pneumocystis carinii
/
Beta-Glucans
Limits:
Animals
Language:
En
Journal:
Antimicrob Agents Chemother
Year:
2024
Document type:
Article
Affiliation country: