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Clinical manifestations of Plasmodium falciparum infection are induced by the asexual stages of the parasite that develop inside red blood cells (RBCs). Because splenic microcirculatory beds filter out altered RBCs, the spleen can innately clear subpopulations of infected or uninfected RBC modified during falciparum malaria. The spleen appears more protective against severe manifestations of malaria in naïve than in immune subjects. The spleen-specific pitting function accounts for a large fraction of parasite clearance in artemisinin-treated patients. RBC loss contributes to malarial anemia, a clinical form associated with subacute progression, frequent splenomegaly, and relatively low parasitemia. Stringent splenic clearance of ring-infected RBCs and uninfected, but parasite-altered, RBCs, may altogether exacerbate anemia and reduce the risks of severe complications associated with high parasite loads, such as cerebral malaria. The age of the patient directly influences the risk of severe manifestations. We hypothesize that coevolution resulting in increased splenic clearance of P. falciparum–altered RBCs in children favors the survival of the host and, ultimately, sustained parasite transmission. This analysis of the RBC–spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated.

Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the “physical fitness test” to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria. Significance The 3D opening of the interendothelial slit in human spleen creates a physical fitness test for red blood cells (RBCs) and clears them from circulation if their geometry and deformability are altered. We present a unique computational framework for the development of prognostic markers for diseases that alter RBC physical characteristics and identify quantitative limits for splenic slit clearance. Our work shows how the splenic slit determines distributions of size and shape of healthy RBCs. Our work lays the groundwork for systematic reconstruction of RBC navigation in the human spleen with consequences for a variety of acute and chronic medical conditions associated with hereditary alterations of RBCs, infectious diseases, and cancers.

Summary: The spleen has a combined function of immune defence and quality control of senescent or altered red cells. It is the first organ injured in sickle cell anaemia (SCA) with evidence of hyposplenism present before 12 months in the majority of children. Repeated splenic vaso‐occlusion leads to fibrosis and progressive atrophy of the organ (autosplenectomy), which is generally complete by 5 years in SCA. The precise sequence of pathogenic events leading to hyposplenism is unknown. Splenic injury is generally silent and progressive. It can be clinically overt with acute splenic sequestration of red cells, an unpredictable and life‐threatening complication in infants. Splenomegaly, with or without hypersplenism, can also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism indirectly increases the risk of vaso‐occlusion or other circulatory complications remains to be determined.

Plasmodium vivax threatens nearly half the world’s population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.

We developed a microtitration method to determine the parasite burdens in homogenized organs of mice infected with Leishmania infantum. This method proved more sensitive than direct enumeration of amastigotes in stained organs, was appropriate for describing the kinetics of infection, and can be considered for physiopathological or pharmaceutical experimental studies.