Parasite Burden and CD36-Mediated Sequestration Are Determinants of Acute Lung Injury in an Experimental Malaria Model

PLoS Pathogens

Kevin C. Kain¹  Samir N. Patel¹  Timothy R. Hughes²  Lourdes Peña-Castillo²  Fiona E. Lovegrove³  John T. Ruzinski⁴  W. Conrad Liles⁴  Sina A. Gharib⁴ 

[1] Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada;Department of Medicine, University of Washington, Seattle, Washington, United States of America;Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada;McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

关键词: Parasitic diseases;    Malaria;    Malarial parasites;    Mouse models;    Cerebral malaria;    Parasitemia;    Inflammation;    Cytokines;   

DOI  :  10.1371/journal.ppat.1000068

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY