We developed a novel model of MA-ARDS with many similarities to human MA-ARDS and without cerebral complications. This contrasts with the more classical model with P. berghei ANKA, characterized by fulminant cerebral malaria. Hence, infection with P. berghei NK65 generates a broader time window to study the pathogenesis and to evaluate candidate treatments. The finding that high doses of dexamethasone cured MA-ARDS suggests that it might be more effective against MA-ARDS than it was in the clinical trials for cerebral malaria.

Key Points Platelet-derived VWF alone mediates full ischemic stroke injury in mice via a GPIb-dependent mechanism. Platelet-derived VWF does not significantly contribute to normal thrombosis and hemostasis in mice.

Background: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lethal complication of severe malaria, characterized by marked pulmonary inflammation. Patient studies have suggested a link between von Willebrand factor (VWF) and malaria severity. Objectives:To investigate the role of VWF in the pathogenesis of experimental MA-ARDS.Methods: Plasmodium berghei NK65-E (PbNK65) parasites were injected in Vwf +/+ and Vwf −/− mice. Pathological parameters were assessed following infection. Results:In accordance with patients with severe malaria, plasma VWF levels were increased and ADAMTS13 activity levels were reduced in experimental MA-ARDS.ADAMTS13-and plasmin-independent reductions of high molecular weight VWF multimers were observed at the end stage of disease. Thrombocytopenia was VWFindependent because it was observed in both Vwf +/+ and Vwf −/− mice. Interestingly, Vwf −/− mice had a shorter survival time compared with Vwf +/+ controls following PbNK65 infection. Lung edema could not explain this shortened survival because alveolar protein levels in Vwf −/− mice were approximately two times lower than in Vwf +/+ controls. Parasite load, on the other hand, was significantly increased in Vwf −/− mice compared with Vwf +/+ mice in both peripheral blood and lung tissue. In addition, anemia was only observed in PbNK65-infected Vwf −/− mice. Of note, Vwf −/− mice presented with two times more reticulocytes, a preferential target of the parasites. Conclusions:This study suggests that parasite load together with malarial anemia, rather than alveolar leakage, might contribute to shortened survival in PbNK65-infected Vwf −/− mice. VWF deficiency is associated with early reticulocytosis following PbNK65 infection, which potentially explains the increase in parasite load. K E Y W O R D S malaria, Plasmodium berghei NK65, respiratory distress syndrome, reticulocytes, von Willebrand Factor | 1373 KRAISIN et Al.