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- Title
Skeleton binding protein-1-mediated parasite sequestration inhibits spontaneous resolution of malaria-associated acute respiratory distress syndrome.
- Authors
Possemiers, Hendrik; Pham, Thao-Thy; Coens, Marion; Pollenus, Emilie; Knoops, Sofie; Noppen, Sam; Vandermosten, Leen; D'haese, Sigrid; Dillemans, Luna; Prenen, Fran; Schols, Dominique; Franke-Fayard, Blandine; Van den Steen, Philippe E.
- Abstract
Malaria is a hazardous disease caused by Plasmodium parasites and often results in lethal complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Parasite sequestration in the microvasculature is often observed, but its role in malaria pathogenesis and complications is still incompletely understood. We used skeleton binding protein-1 (SBP-1) KO parasites to study the role of sequestration in experimental MA-ARDS. The sequestration-deficiency of these SBP-1 KO parasites was confirmed with bioluminescence imaging and by measuring parasite accumulation in the lungs with RT-qPCR. The SBP-1 KO parasites induced similar lung pathology in the early stage of experimental MA-ARDS compared to wildtype (WT) parasites. Strikingly, the lung pathology resolved subsequently in more than 60% of the SBP-1 KO infected mice, resulting in prolonged survival despite the continuous presence of the parasite. This spontaneous disease resolution was associated with decreased inflammatory cytokine expression measured by RT-qPCR and lower expression of cytotoxic markers in pathogenic CD8+ T cells in the lungs of SBP-1 KO infected mice. These data suggest that SBP-1-mediated parasite sequestration and subsequent high parasite load are not essential for the development of experimental MA-ARDS but inhibit the resolution of the disease. Author summary: Malaria is still a severe global disease with more than 200 million cases and 400 000 deaths each year. Plasmodium falciparum is the species responsible for most malaria deaths globally. The propensity of these parasites to sequester in peripheral vascular beds is assumed to play an important role in disease severity and mortality. Although sequestration has been observed in lungs of malaria patients, its role in the pathogenesis of MA-ARDS, a severe lung complication in malaria, was previously unknown. Therefore, we used sequestration-deficient SBP-1 KO Plasmodium berghei NK65 parasites to study the role of sequestration in experimental MA-ARDS. We observed that MA-ARDS developed similarly in WT and SBP-1 KO infected mice, but the majority of SBP-1 KO-infected mice were able to resolve the lung pathology despite the continuous presence of the parasite. This coincided with a prolonged survival, a decrease in inflammatory cytokine expression and lower expression of cytotoxicity markers in pathogenic CD8+ T cells. These results give important new insights in the role of parasite sequestration in malaria pathology.
- Subjects
MALARIA; ADULT respiratory distress syndrome; PLASMODIUM; PARASITES; PLASMODIUM berghei
- Publication
PLoS Pathogens, 2021, Vol 17, Issue 11, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1010114