Aims:
To identify mechanisms of organ dysfunction and severe clinical disease in malaria caused by all major species of Plasmodium causing malaria in humans
Summary:
In one of the longest programs at Menzies, we collaborate with partners in Indonesia, Malaysia and countries across Africa to discover mechanisms underlying severe disease from malaria. We compare mechanisms across the three major parasite species causing severe malaria in humans: Plasmodium falciparum, P. vivax and P. knowlesi
Our research has found:
Over the last 30 years this program has identified endothelial dysfunction, impaired vascular nitric oxide bioavailability and endothelial activation as a key mechanisms of impaired tissue perfusion, organ dysfunction and severe malaria in all species of malaria. In severe falciparum malaria, sequestered parasite biomass and endothelial activation are both independent predictors of severe malaria and death. We have identified key mechanisms underlying anaemia and severe anaemia in falciparum, knowlesi and vivax malaria, mostly from loss of uninfected red blood cells, including reduced red blood cell deformability, altered red blood cell surface and splenic retention of uninfected red blood cells. Mechanisms of acute kidney injury in falciparum and knowlesi malaria include intravascular haemolysis and endothelial activation. Inflammatory responses to parasites within pulmonary capillaries causes acute lung injury, increased vascularpermeability and impaired gas transfer, especially after the start of anatimalarial chemotherapy.
Implications for policy and practice:
Identifying mechanisms of disease has resulted in clinical trials of adjunctive therapy for severe malaria caused by falciparum and knowlesi malaria. These include trials of arginine in severe falciparum malaria, and paracetamol to reduce haemolysis-associated acute kidney injury in knowlesi and falciparum malaria.
Chief Investigator:
Contact info:
nicholas.anstey@menzies.edu.au
Project date:
1997-present