Funders:

Collaborators:

Infectious Diseases Society Kota Kinabalu Sabah (Malaysia), Timika Malaria Research Facility (Papua, Indonesia), Infectious Diseases Research Collaboration (Uganda)
 

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:

Nicholas Anstey

Contact info:

nicholas.anstey@menzies.edu.au 

Project date:

1997-present

1. Kho, S, Rini, H, Kambuaya, NN, …. Anstey NM. (2026). Splenic tropism of Plasmodium vivax in acute infection and spleen-attenuated systemic inflammation. bioRxiv, 2026.03.25.714340. 
2. Rathnam JTT, Grigg MJ, Dondorp AM, William T, Rajasekhar M, Rajahram G, Simpson JA, Barber BE, Anstey NM. Reduced Red Blood Cell Deformability in Vivax Malaria. J Infect Dis. 2025 Mar 17;231(3):e566-e569. doi: 10.1093/infdis/jiae490. PMID: 39374370; PMCID: PMC11911793.
3. Anstey NM, Tham WH, Shanks GD, Poespoprodjo JR, Russell BM, Kho S. The biology and pathogenesis of vivax malaria. Trends Parasitol. 2024 Jul;40(7):573-590. doi: 10.1016/j.pt.2024.04.015. Epub 2024 May 15. PMID: 38749866.
4. Kho S, Siregar NC, Qotrunnada L, Fricot A, Sissoko A, Shanti PAI, Candrawati F, Kambuaya NN, Rini H, Andries B, Hardy D, Margyaningsih NI, Fadllan F, Rahmayenti DA, Puspitasari AM, Aisah AR, Leonardo L, Yayang BTG, Margayani DS, Prayoga P, Trianty L, Kenangalem E, Price RN, Yeo TW, Minigo G, Noviyanti R, Poespoprodjo JR, Anstey NM*, Buffet PA*. Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria. Am J Hematol. 2024 Feb;99(2):223-235. doi: 10.1002/ajh.27152. Epub 2023 Nov 27. PMID: 38009287; PMCID: PMC10952982.
5. Poespoprodjo JR, Douglas NM, Ansong D, Kho S, Anstey NM. Malaria. Lancet. 2023 Dec 16;402(10419):2328-2345. doi: 10.1016/S0140-6736(23)01249-7. Epub 2023 Nov 2. PMID: 37924827.
6. Anstey NM, Grigg MJ, Rajahram GS, Cooper DJ, William T, Kho S, Barber BE. Knowlesi malaria: Human risk factors, clinical spectrum, and pathophysiology. Adv Parasitol. 2021;113:1-43. doi: 10.1016/bs.apar.2021.08.001. Epub 2021 Aug 28. PMID: 34620381; PMCID: PMC9299579.
7. Barber BE, Grigg MJ, Piera KA, William T, Cooper DJ, Plewes K, Dondorp AM, Yeo TW, Anstey NM. Intravascular haemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury. Emerg Microbes Infect. 2018 Jun 6;7(1):106. doi: 10.1038/s41426-018-0105-2. PMID: 29872039; PMCID: PMC5988665.
8. Kho S, Qotrunnada L, Leonardo L, Andries B, Wardani PAI, Fricot A, Henry B, Hardy D, Margyaningsih NI, Apriyanti D, Puspitasari AM, Prayoga P, Trianty L, Kenangalem E, Chretien F, Safeukui I, Del Portillo HA, Fernandez-Becerra C, Meibalan E, Marti M, Price RN, Woodberry T, Ndour PA, Russell BM, Yeo TW, Minigo G, Noviyanti R, Poespoprodjo JR, Siregar NC, Buffet PA*, Anstey NM*. Hidden Biomass of Intact Malaria Parasites in the Human Spleen. N Engl J Med. 2021 May 27;384(21):2067-2069. doi: 10.1056/NEJMc2023884. PMID: 34042394.
9. Yeo TW, Weinberg JB, Lampah DA, Kenangalem E, Bush P, Chen Y, Price RN, Young S, Zhang HY, Millington D, Granger DL, Anstey NM. Glycocalyx Breakdown Is Associated With Severe Disease and Fatal Outcome in Plasmodium falciparum Malaria. Clin Infect Dis. 2019 Oct 30;69(10):1712-1720. doi: 10.1093/cid/ciz038. PMID: 30753363; PMCID: PMC6821254.
10. Yeo TW, Lampah DA, Kenangalem E, Tjitra E, Price RN, Weinberg JB, Hyland K, Granger DL, Anstey NM. Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation. PLoS Pathog. 2015 Mar 12;11(3):e1004667. doi: 10.1371/journal.ppat.1004667. PMID: 25764397; PMCID: PMC4357386.
11. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, Price RN, Duffull SB, Celermajer DS, Anstey NM. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17097-102. doi: 10.1073/pnas.0805782105. Epub 2008 Oct 28. PMID: 18957536; PMCID: PMC2575222.