Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria
Fiona E Lovegrove1, Sina A Gharib, Lourdes Peña-Castillo
1Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Although acute lung injury (ALI) is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM); however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar-capillary membrane barrier-the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36(-/-) mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality.
Insights
Acute lung injury (ALI) in severe malaria is linked to parasite burden and CD36-mediated lung sequestration in mice. Distinct genetic factors influence susceptibility to ALI and cerebral malaria (CM).
Area of Science:
- Pathology
- Immunology
- Genetics
Background:
- Acute lung injury (ALI) is a frequent complication of severe malaria, yet its molecular underpinnings remain unclear.
- Existing animal models primarily focus on cerebral malaria (CM), lacking a definitive model for malaria-induced lung injury.
- Understanding malaria-induced ALI is crucial for addressing significant morbidity and mortality associated with severe malaria.
Purpose of the Study:
- To establish and characterize a murine model for studying acute lung injury (ALI) in experimental malaria.
- To investigate the molecular mechanisms and pathological features of malaria-induced ALI.
- To identify genetic factors and parasite-related mechanisms contributing to ALI in malaria.
Main Methods:
- Utilized bronchoalveolar lavage (BAL), histopathology, and gene expression analysis in Plasmodium berghei ANKA (PbA)-infected mice.
- Examined BAL fluid for protein and cell content, and lung tissue for inflammatory markers and gene expression changes.
- Assessed ALI severity across different inbred mouse strains and in CD36-deficient mice.
Main Results:
- PbA infection led to increased IgM and protein in BAL fluid, indicating alveolar-capillary barrier disruption, a hallmark of ALI.
- Histopathology revealed septal inflammation without significant neutrophil infiltration, differing from sepsis-induced ALI.
- Gene expression analysis showed upregulation of immune response and defense genes; ALI severity correlated with parasite burden and CD36-mediated lung sequestration.
Conclusions:
- Parasite burden and CD36-mediated lung sequestration are key drivers of ALI in experimental murine malaria.
- Susceptibility to malaria-induced ALI and CM is influenced by distinct genetic factors.
- This study provides a valuable model for investigating malaria-induced lung injury and its associated genetic determinants.
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