Skeleton binding protein-1-mediated parasite sequestration inhibits spontaneous resolution of malaria-associated acute respiratory distress syndrome

PLoS Pathog. 2021 Nov 29;17(11):e1010114. doi: 10.1371/journal.ppat.1010114. eCollection 2021 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Progression
  • Female
  • Lung / metabolism
  • Lung / parasitology*
  • Lung / pathology
  • Malaria / complications*
  • Malaria / parasitology
  • Male
  • Membrane Proteins / deficiency*
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium berghei / pathogenicity*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Respiratory Distress Syndrome / metabolism
  • Respiratory Distress Syndrome / parasitology
  • Respiratory Distress Syndrome / pathology
  • Respiratory Distress Syndrome / prevention & control*

Substances

  • Membrane Proteins
  • Pfsbp1 protein, Plasmodium falciparum
  • Protozoan Proteins

Grant support

This work has been supported by the Research Foundation Flanders (F.W.O. Vlaanderen, URL: https://www.fwo.be/) (Grant No G0C9720N to PEVdS) and the Research Fund (C1 project C16/ 17/010 to PEVdS) of the KU Leuven (URL: https://www.kuleuven.be/kuleuven/). HP and LD hold an aspirant PhD fellowship of the F.W.O. Vlaanderen, LV an postdoctoral fellowship of the F.W.O. Vlaanderen and EP a recipient of the L’Oréal-Unesco Women for Sciences PhD fellowship. TP held an aspirant PhD fellowship of the F.W.O. Vlaanderen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.