부산대학교 도서관

Plasmodium parasites cause malaria, a global health disease that is responsible for more than 200 million clinical cases and 600 000 deaths each year. Most deaths are caused by various complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite the very rapid and efficient killing of parasites with antimalarial drugs, 15% of patients with complicated malaria succumb. This stresses the importance of investigating resolution mechanisms that are involved in the recovery from these complications once the parasite is killed. To study the resolution of MA-ARDS, P. berghei NK65-infected C57BL/6 mice were treated with antimalarial drugs after onset of symptoms, resulting in 80% survival. Micro-computed tomography revealed alterations of the lungs upon infection, with an increase in total and non-aerated lung volume due to edema. Whole body plethysmography confirmed a drastically altered lung ventilation, which was restored during resolution. Single-cell RNA sequencing indicated an increased inflammatory state in the lungs upon infection, which was accompanied by a drastic decrease in endothelial cells, consistent with CD8+ T cell mediated killing. During resolution, anti-inflammatory pathways were upregulated and proliferation of endothelial cells was observed. MultiNicheNet interactome analysis identified important changes in the ligand-receptor interactions during disease resolution that warrant further exploration in order to develop new therapeutic strategies. In conclusion, our study provides insights in pro-resolving pathways that limit inflammation and promote endothelial cell proliferation in experimental MA-ARDS. This information may be useful for the design of adjunctive treatments to enhance resolution after Plasmodium parasite killing by antimalarial drugs. Author summary: Malaria is a global disease caused by Plasmodium parasites, resulting each year in more than 600 000 deaths, mainly caused by complications. Despite rapidly acting antimalarial drugs, 15% of patients who developed a complication still die. Therefore, we aimed to investigate the recovery from a malaria complication, namely malaria-associated acute respiratory distress syndrome (MA-ARDS), after parasite killing with antimalarial drugs. In our mouse model, lung alterations were observed upon infection and lung ventilation was restored during the recovery phase. Moreover, an increased inflammatory state in the lungs was observed upon infection, which was accompanied by a drastic decrease in number of endothelial cells. During resolution, anti-inflammatory pathways were upregulated and remaining endothelial cells multiplied to restore the blood vessel wall. Therefore, promotion of resolution and proliferation of endothelial cells may be an interesting approach to design novel treatments that can be used in combination with the antimalarial drugs. [ABSTRACT FROM AUTHOR]