Immunopathology and dexamethasone therapy in a new model for malaria-associated acute respiratory distress syndrome

Abstract

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a common lethal complication of malaria, which often develops during or after anti-malarial chemotherapy. Until now, no efficient treatments are available for this complication and its pathogenesis remains poorly understood. The only mouse model to study MA-ARDS available was by infection with P. berghei ANKA (PbANKA), which is characterized by fulminant cerebral malaria and early death, before MA-ARDS is fully developed. We established a novel model of MA-ARDS in C57Bl/6 mice by infection with Plasmodium berghei NK65 (PbNK65), in which no cerebral malaria occurs. Hence, infection with PbNK65 generates a broader time window to study the disease mechanisms and, more importantly, to evaluate candidate treatments. PbNK65 infection resulted in leukocyte accumulation, extensive edema and hemorrhage in the lungs. The pulmonary expression of several cytokines and chemokines was increased to a higher level than in mice infected with P. chabaudi AS, which does not cause MA-ARDS. By depletion experiments, CD8+ T lymphocytes were shown to be pathogenic. We document that high doses of dexamethasone (DEX) block MA-ARDS through inhibition of lymphocyte proliferation and by decreasing the expression of chemoattractants for monocytes/macrophages. DEX administration cured MA-ARDS even when given after appearance of the lung complication. In conclusion, PbNK65 infection of C57Bl/6 mice is an important novel animal model for MA-ARDS, with many similarities to human MA-ARDS. The finding that DEX displayed therapeutic effects even when administered after the initiation of MA-ARDS is in contrast with the known effects of DEX in the mouse model for cerebral malaria, in which preventive administration is required to inhibit the neurological pathology. This suggests that DEX may be more successful in the treatment of human MA-ARDS than it was in the clinical trials for cerebral malaria.