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.
Highlights
Malaria is a severe disease caused by Plasmodium parasites and affects 200 million people each year, with more than 400 000 deaths [1]
skeleton binding protein-1 (SBP-1) is essential for the transport of adhesins to the surface of the infected red blood cells (iRBC) and genetic deletion of SBP-1 leads to a decreased sequestration ability [8]
Parasites were quantified in the lungs of mice by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) 22 hours after intravenous (i.v.) injection with 107 or 108 WT or SBP-1 KO schizonts
Summary
Malaria is a severe disease caused by Plasmodium parasites and affects 200 million people each year, with more than 400 000 deaths [1]. Despite the availability of good antimalarial treatments and prevention measures, these numbers are stalling and both transmission and severe disease still remain in 91 countries. MA-ARDS is a severe lung complication with a high lethality rate, characterized by diffuse alveolar inflammation, damage to the alveolar-capillary membrane, microhemorrhages and vasogenic edema in the lungs [2]. A mouse model for experimental MA-ARDS was developed. In this model, C57BL/6 mice are infected with Plasmodium berghei NK65 (PbNK65) parasites, which cause lethal pulmonary inflammation with protein-rich interstitial and alveolar edema [3]
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