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EphA2Extra-HC04 cells enhanced P. vivax liver-stage infection. (A) Fold increase of P. vivax infection of the two EphA2Extra-HC04 clones relative to the original HC-04. Error bars represent S.E.M. of 8 biological replicates. The p-value for two-tail paired t-test between EphA2Extra-HC04 cell clones and original HC-04. (B) P. vivax-infected EphA2Extra-HC04 (top) and original HC-04 (bottom) were labeled with a HA-tag antibody (green). Liver-stage parasites were labeled with a UIS4 antibody (red). Nuclei were stained with DAPI (blue). The scale bar represents 5 μm. (C) The size distribution of liver-stage parasites in each cell line. The diameters of intrahepatic parasites on day 4 post-infection were pooled from eight P. vivax clinical isolates. Dashed lines represent the medians; dotted lines delimit the interquartile ranges. ****Indicates a p-value < 0.0001 and ns indicates a non-significant test result (p = 0.0761) by the Mann–Whitney test between the indicated pair.
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.
