The human spleen significantly influences red blood cell (RBC) dynamics due to its ability to retain and/or remove RBCs from peripheral blood circulation. This filtering can mediate a range of malaria disease manifestations, depending on the physiological properties of the spleen. Data collected from patients undergoing splenectomy in Papua, Indonesia, revealed that in asymptomatic infections the spleen harboured substantially more infected RBCs than were circulating in the peripheral blood and that the spleen is also congested with uninfected RBCs. We hypothesise that two conditions hold for the spleen to retain such a high proportion of infected and uninfected RBCs: (i) the retention rate of RBCs is significantly higher than in uninfected patients; and (ii) phagocytosing macrophages cannot clear all of the infected RBCs from the spleen. In this paper, we present a mathematical model of RBC dynamics that includes, for the first time, the spleen as a compartment capable of retaining large numbers of infected and uninfected RBCs in Plasmodium falciparum and P. vivax infections. By calibrating the model to the Papuan data, we demon-strate that the spleen plays a significant role in removing not only infected RBCs but also uninfected RBCs. Uninfected RBC retention in the spleen, attributable to malaria, is substantially higher than circulating RBC loss due to parasitisation, for infections by both Plasmodium species. In chronic infections, the ratio of circulating uninfected RBCs lost to splenic retention per circulating uninfected RBC lost to parasitisation is 17:1 for P. falciparum and 82:1 for P. vivax. These ratios are larger than previously published estimates for acute clinical infections.

The authors have declared no competing interest.

J.A.S. is funded by an Australian NHMRC Leadership Investigator Grant (1196068). R.M., M.R. and D.J.P. are partly funded through Australian NHMRC grants 2024622 (Australian Centre of Research Excellence for Malaria Elimination) and 2018654. S.K. was supported by an Australian NHMRC Emerging Leadership Investigator Grant (2025376) and Australian NHMRC grant 2019153. N.M.A. is supported by Australian NHMRC grant 1037304. B.B is funded by an Australian NHMRC Emerging Leadership Investigator Grant (2016792). P.A.B. is funded by Agence Nationale de la Recherche grant ANR-24-CE17-2900-01 ("HepCMal").

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