ISGlobal researchers Hernando A. del Portillo and Carmen Fernández, both with joint affiliation with the Germans Trias i Pujol Research Institute (IGTP), have participated in studies that have been described in two ground-breaking publications. The new studies change the accepted facts about malaria vivax and resolves long-standing inconsistencies in previous thinking on the biology of Plasmodium vivax. The work focuses on the spleen, which has been thought to be the organ that cleared malaria parasites from the blood; the new data shows that in fact it is also a reservoir and nursery for the parasite.
Most cases of malaria are caused by the single celled parasites Plasmodium falciparum and Plasmodium vivax, which enter the blood via mosquito bites. The malaria caused by P. vivax is neither as virulent or as severe as P. falciparum malaria and less research has been carried out on it, but it is known to lie dormant in the liver and cause relapse and also death in severe cases. Current understanding of the disease is that there is a low level of P. vivax in circulating blood because the parasite targets reticulocytes, immature red blood cells, which are mainly found in bone marrow. The spleen destroys the parasites, especially after malaria treatment and has been thought to be the site of their elimination from the blood until now.
In a letter published in the New England Journal of Medicine, the authors describe a previously undetected biomass of both P. falciparum and P. vivax in the spleen. The group studied the spleens of people infected with both parasites and compared this with circulating blood from the same patients and from malaria free individuals. Using different methods, they ascertained that, contrary to previous evidence, there are far larger numbers of parasites in the spleen than in the blood, more so for P. vivax than P. falciparum. They conclude that chronic vivax malaria is an infection of the spleen, not the blood.
In a more extensive paper in the journal PLOS Medicine, the same team, led by Nicholas Anstey from the Menzies School of Health Research and Charles Darwin University, Australia, extends the results of their findings in P. vivax. They examined both the different stages of reticulocyte and different phases of P. vivax in the spleen during its complex life cycle. The conclusions are that P. vivax, far from being destroyed in the spleen, has adapted to survive and also to replicate in this organ, reversing the assumptions made until now.
“Taking part in this study is an immense satisfaction as we have originally postulated the existence of intrasplenic infections in P. vivax,” says Hernando A. del Portillo, ICREA researcher and leader of the Plasmodium vivax and Exosome Research (PVREX). Several of the group’s research lines over the last 20 years have concentrated on P. vivax and particularly aspects of adhesion of the parasite in hemopoietic tissues.
“The accepted wisdom on the roles of the liver and spleen in P. vivax have become more and more difficult to justify over the years. With the intense tropism of P. vivax for reticulocytes, we have suspected that they had a previously undescribed role in the spleen. These results definitively change the understanding of the biology of the parasite and the role of the spleen, it is ground-breaking,” adds Carmen Fernández-Becerra, Co-Leader of the PVREX group.
These results have important implications for identifying new drug targets and drug delivery platforms, as parasites in this location are largely sheltered from antimalarial drugs. It also has important implications for the identification of biomarkers of asymptomatic chronic infections to improve diagnostic methods. As working with the human spleen is technically and ethically difficult, new technologies need to be developed to get molecular insights of these intrasplenic infections, thus ultimately contributing to the elimination of malaria.
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
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, Brousse V, 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. Evaluation of splenic accumulation and colocalization of immature reticulocytes and Plasmodium vivax in asymptomatic malaria: A prospective human splenectomy study. PLoS Med. 2021 May 26;18(5):e1003632. doi: 10.1371/journal.pmed.1003632. eCollection 2021 May. PMID: 34038413