Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to Pneumocystis carinii β-glucans

• Published in: Antimicrobial agents and chemotherapy 2024-02, Vol.68 (2), p.e0081123
• Main Authors: Kottom, Theodore J, Carmona, Eva M, Limper, Andrew H
• Format: Article
• Language: English
• Subjects: Animals; Benzamides; beta-Glucans - metabolism; Clinical Therapeutics; Eukaryotic Cells; Immunocompromised Host; Macrophages - microbiology; Mice; Niacinamide - analogs & derivatives; Pneumocystis; Pneumocystis carinii; Pneumonia, Pneumocystis - microbiology; Receptor Protein-Tyrosine Kinases; Receptor, EphA2
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.00811-23

the fungus that causes pneumonia (PJP), is a leading cause of morbidity and mortality in immunocompromised individuals. We have previously shown that lung epithelial cells can bind spp. β-glucans via the EphA2 receptor, resulting in activation and release of proinflammatory cytokines. Herein, we show that spp. β-glucans activation of the inflammatory signaling cascade in macrophages can be pharmacodynamically inhibited with the EphA2 receptor small-molecule inhibitor ALW-II-41-27. , when ALW-II-41-27 is administrated via intraperitoneal to mice prior to the administration of highly proinflammatory β-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 β-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.