Aims:
  • To dissect the underlying pathobiology of the hidden splenic malaria parasite reservoir in humans
  • To target the hidden splenic reservoir to reduce global malaria burden
Objectives:
  • Elucidate the genetic diversity of malaria parasites in the spleen
  • Investigate the mechanisms of splenic parasite survival
  • Identify unique molecular signatures of splenic malaria parasites for improved malaria diagnostics, treatment and control strategies
Summary: 

Global malaria elimination is complicated by the existence of hidden infectious reservoirs. In a paradigm-shifting discovery, we has revealed that the human spleen is a major parasite reservoir in individuals naturally-infected with Plasmodium falciparum and P. vivax. The magnitude of splenic parasite concealment was substantial, reshaping the vision of malaria as an infection developing predominantly in the spleen rather than exclusively in the blood, sustained by a novel endosplenic lifecycle. Concerningly, our preliminary data suggest that splenic parasites likely display distinct behaviours that significantly impact our ability to fully detect and treat malaria effectively. We hypothesise that splenic malaria parasites are genetically more diverse than peripheral blood populations, and possess unique molecular signatures related to reduced drug susceptibility, along with an underlying ability to adapt, survive and replicate in an environment that is traditionally recognised as detrimental. We also propose that dormant/metabolically-inactive parasites can develop in the spleen and later reactivate to give rise to illness. 

We have established the only known prospective cohort of matching spleen tissue and peripheral blood from untreated individuals infected with malaria parasites. The overarching goal of our studies is to elucidate the fundamental biology of the newly-discovered splenic Plasmodium population in humans, and identify novel approaches to detect and overcome splenic parasite survival. 

Implications for policy and practice:

In addition, with the spleen harbouring the majority of malaria parasite biomass in humans, it represents an additional major hurdle to malaria elimination. Our program of work may lead to changes in malaria control and treatment.

Our research has found:

The spleen program at Menzies may reveal novel mechanisms in Plasmodium biology, potentially identifying parasite phenotypes in the spleen with reduced susceptibility to current antimalarial drugs and those with features of dormancy, and a potential splenic role in emergence of drug resistance. the presence of a large hidden biomass of viable malaria parasites in the spleen, accounting for the large majority of total-body parasite biomass in humans. We have also uncovered the existence of a novel Plasmodium lifecycle occurring in the spleen in natural infections. These paradigm shifts have transformed our understanding of malaria biology and has revealed a new hurdle to malaria elimination.

Chief Investigator: 
Project Manager: 
  • Catherine Martel/Rebecca Reagan
Contact information: 
  • Catherine.Martel@menzies.edu.au
Project dates:

2015-ongoing

Funders: 
  • National Health and Medical Research Council

Collaborators:
  • Papuan Health and Community Development Foundation
  • Pasteur Institute
  • Exeins Health Initiative 
  • Eijkman, Gadjah Mada University
  •  Burnet Institute
  • QIMR-B
  • WEHI
  • Unimelb
     

 

  • Kho S., Qotrunnada L., Leonardo L., Andries B., Wardani P.A.I., Fricot A., Henry B., Hardy D., Margyaningsih N.I., Apriyanti D., Puspitasari A.M., Prayoga P., Trianty L., Kenangalem E., Chretien F., Safeukui I., Del Portillo H.A., Fernandez-Becerra C., Meibalan E., Marti M., Price R.N., Woodberry T., Ndour P.A., Russell B.M., Yeo T.W., Minigo G., Noviyanti R., Poespoprodjo J.R., Siregar N.C., *Buffet P.A., *Anstey N.M. Hidden biomass of intact malaria parasites in the human spleen. New Engl J Med, 2021 May; 384(21):2067-2069.
  • Kho S., Qotrunnada L., Leonardo L., Andries B., Wardani P.A.I., Fricot A., Henry B., Hardy D., Margyaningsih N.I., Apriyanti D., Puspitasari A.M., Prayoga P., Trianty L., Kenangalem E., Chretien F., Brousse V., Safeukui I., Del Portillo H.A., Fernandez-Becerra C., Meibalan E., Marti M., Price R.N., Woodberry T., Ndour P.A., Russell B.M., Yeo T.W., Minigo G., Noviyanti R., Poespoprodjo J.R., Siregar N.C., *Buffet P.A., *Anstey N.M. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: a prospective human splenectomy study. PLOS Med, 2021 May; 18(5):e1003632.
  • Kho S., Andries B., Poespoprodjo J.R., Commons R.J., Shanti P.A.I., Kenangalem E., Douglas N.M., Simpson J.A., Sugiarto P., Anstey N.M., Price R.N. High risk of Plasmodium vivax malaria following splenectomy in Papua, Indonesia. Clin Infect Dis, 2019 Jan; 68(1): 51-60. 
  • Kambuaya, NM., Rini H., Shanti PAI., Alexander K., Candrawati F., Prayoga P., Leonardo L., Margayani D., Yayang BTG., Kenangalem E., Buffet PA., Anstey NM., Poespoprodjo JR., Kho S. Case Report: Severe Plasmodium vivax Malaria after Splenectomy. Am J Trop Med Hyg, 2023 June 20;109(2):284-287.