Abstract
BackgroundThe mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.MethodsWe first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.ResultsThe results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.ConclusionOur data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.
Highlights
Malaria (Plasmodium. falciparum) infects 200 to 300 million people globally and kills approximately 900,000 every year
Our data indicate that Heme/Heme oxygenase (HO)-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria
We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality
Summary
Malaria (Plasmodium. falciparum) infects 200 to 300 million people globally and kills approximately 900,000 (mostly children) every year. Current anti-malaria drugs, such as quinine and artemisinin derivatives can effectively clear malaria parasites in blood, a significant numbers of severe malaria patients including CM patients die or develop severe sequelae regardless of treatment [1,2]. It is not clear which factors exacerbate mortality among this subset of CM patients, important questions remain to be answered concerning the mechanism(s) of malaria pathogenesis and development of effective therapies. Existing anti-malaria therapy focus on clearance of parasites from blood This strategy does not prevent secondary deleterious effects such as neurological disorders and cognitive problems caused by parasite derived factors. We tested the hypothesis that these factors share common signaling pathways and may be mutually regulated
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