Figure - available from: Scientific Reports
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Schematic illustrations of recombinant EpA2 constructs. HA: HA-tag, myc myc-tag, LBD: ligand binding domain, CysRich: cysteine-rich domain, FNIII: fibronectin III repeat, Kinase: kinase domain, SAM: sterile α-motif domain, PDZ: PDZ-binding motif. The native TMD of EphA2 is depicted in blue; the PDGFR TMD is in orange. The figure was created with BioRender.com.
Source publication
The liver is the first destination of malaria parasites in humans. After reaching the liver by the blood stream, Plasmodium sporozoites cross the liver sinusoid epithelium, enter and exit several hepatocytes, and eventually invade a final hepatocyte host cell. At present, the mechanism of hepatocyte invasion is only partially understood, presenting...
Citations
... Remarkably, we noted that ALW-II-41-27 could indeed significantly reduce TNF-alpha protein levels in the lungs versus the vehicle control group in yeast β-glucan-challenged mouse lungs (Fig. 6). A number of reports have shown the importance of the EphA2 receptor pathway in organism attachment and host immune recognition to microbial pathogens (12,(33)(34)(35). Recently, we also have reported that EphA2 can bind Pneumocystis glucans and is involved in lung epithelial cell proinflammatory response to the organism's cell wall carbohydrate (1). ...
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. β-glucans via the EphA2 receptor, resulting in activation and release of proinflammatory cytokines. Herein, we show that in vivo Pneumocystis 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. In vitro, when ALW-II-41-27 is administrated via intraperitoneal to mice prior to the administration of highly proinflammatory Saccharomyces cerevisiae 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.
