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Review
. 2011 Jan 13;117(2):381-92.
doi: 10.1182/blood-2010-04-202911. Epub 2010 Sep 17.

The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology

Pierre A Buffet  1 , Innocent Safeukui, Guillaume Deplaine, Valentine Brousse, Virginie Prendki, Marc Thellier, Gareth D Turner, Odile Mercereau-Puijalon
Affiliations
Review

The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology

Pierre A Buffet et al. Blood. .

Abstract

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 VSports手机版. 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. .

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Figures

Figure 1
Figure 1
The splenon the functional unit of splenic RBC filtration. Blood flow is from top right to bottom left and may follow 2 parallel paths. The fast and closed circulation flows from splenic artery to central arterioles and their branches, then through the perifollicular zone (PFZ), PFZ-to-sinus by-passes, sinus lumens, postsinusal veinules that join into the splenic vein, and accounts for 80%-90% of the splenic blood flow. The slow open circulation has at least 2 specificities: (i) a microcirculatory structure devoid of endothelial cells where cord macrophages, and reticular cells survey the slowly migrating blood cells and (ii) narrow and short interendothelial slits in the sinus wall that RBC must cross to get back to the general circulation. The splenon displays analogies and differences with the nephron (see text). Schematically, the filtering function of the spleen can be divided in 3 successive steps. The “prefiltration step” (1) corresponds to the close contacts between RBCs and macrophages in the cords. RBC retention during this step is putatively triggered by ligand-receptor interactions, including direct recognition of RBC surface alterations and opsonization. The “filtration” step (2) corresponds to the crossing of interendothelial slits. RBC retention here is triggered by mechanical alterations. Undeformable bodies can also be extracted from RBCs in a process called pitting. The “postfiltration” step (3) corresponds to the modifications and processing of retained RBCs. Both the prefiltration and postfiltration steps potentially result in the phagocytosis of abnormal, decorated, or opsonized RBCs. Phagocytosis of parasitized RBCs is an initial step of antigen presentation to immune cells, thereby connecting filtration to the antigen-specific response.
Figure 2
Figure 2
Structure-function correspondences in the slow, open microcirculation. (A) On human spleen sections, the medium-sized central artery (CA) is surrounded by white pulp (here, a lymphoid nodule; LN) made of densely packed white cells, between which no RBCs circulate. In the perifollicular zone (PFZ) that surrounds the white pulp, RBCs are visible within flat, concentric microcirculatory spaces. In the red pulp (RP), typical sinuses (S) are observed. RBCs engaged in the fast, closed circulation transit through the PFZ, whereas RBCs in the open microcirculation navigate slowly in the RP cords before returning to the blood vascular bed by crossing the wall of sinuses. Because direct by-passes exist between the PFZ and sinuses, sinus lumens (sl)—though located in the RP—collect both the fast (closed) and the slow (open) microcirculations (Giemsa-stained human spleen section ×400). (B) Macrophages account for almost half the volume of the cords (co), although approximately 10% of them can be found in the sinus lumen (sl, immunohistochemistry of an isolated-perfused human spleen section using an anti-CD68 primary antibody revealed with a peroxidase secondary antibody, ×400). Because the RP accounts for 75% of spleen volume, an average 150-g human spleen contains approximately 50 g (or 50 mL) of macrophages (ie, approximately 100 times greater than the average 0.5-mL volume of monocytes circulating in the vascular beds). (Ci) The visualization of sinus walls on histologic sections is facilitated by PAS (phosphatase acid shift) staining that highlights the peculiar basal fibers of sinuses, providing a clear separation between cords (co) and sinus lumens (sl) (isolated-perfused human spleen ×1000). The sinus wall is made of elongated endothelial cells surrounded by helical basal fibers. (Cii) In a patient treated with artemisinin derivatives, if the parasite load is high, parasite remnants either pitted from their host RBCs or retained with their host RBC delineate the abluminal side of the sinus wall (D1, PAS-stained post mortem spleen sample, ×400). (Di) On transmission electron microscopy (TEM), the periodic disposition and homogenous aspect of basal fibers (pseudocolored purple), as well as elongated shape of sinus endothelial cells (pseudocolored blue), allows an accurate orientation (isolated-perfused human spleen, ×2000). (Dii) When pitted from an RBC squeezing through an inter endothelial slit in a sinus wall, P falciparum remnants are deposited on the abluminal side of the sinus (PAS-stained section of an isolated-perfused human spleen challenged with artesunate-exposed P falciparum–infected RBCs, ×1000, inset ×2000). These observations confirm that pitting occurs exclusively or very predominantly, whereas RBCs cross the sinus wall and illustrates the unidirectional aspect of sinus wall crossing by RBCs—from cords to sinus lumen.
Figure 3
Figure 3
Interactions of P falciparum–infected RBCs with the microcirculation, and with the spleen during acute and chronic infection in patients with normal or impaired splenic function. (Ai) Simplified frame from Figure 1. For simplicity, all nonsplenic microcirculatory structures—either systemic or pulmonary—have been considered homogenous and are presented as a single microvascular channel at the top of the panel (PFZ MZ: perifollicular or marginal zones; RP: red pulp; interendothelial slits: interendothelial slits). Of note, large vessels correspond to the only compartment that can routinely be explored for the presence of infected RBCs (thin and thick smears, or PCR). Forms observed in the rectangle in the middle of the panel symbolize what is usually observed on patient smears in the corresponding situation. (Aii) Situation in a naïve patient (see text for definition) with a normal spleen function. Interactions are shown separately for the young ring forms (rings, left panel) and the mature forms (right panel). (Aiii) Same situation as above, but integrating the retention of a proportion of rings upstream from interendothelial slits, as recently observed in an ex vivo human spleen model. (Bi-ii) Comparative modeling of situations during the first acute infection in unsplenectomized (Bi top panel identical to panel Aiii) and splenectomized patients (Bii lower panel). (Ci-ii) Comparison of acute infection in immune unsplenectomized (panel Bi identical to panel Aiii) or splenectomized patients still exposed to P falciparum transmission after splenectomy (Bii). (Di-ii) Putative mechanisms of acute malaria attacks occurring a few weeks after splenectomy in chronic carriers no longer exposed to P falciparum transmission.
Figure 4
Figure 4
Ability of RBCs to cross the spleen, dispersion of individual values, and possible variability of the splenic detection threshold in the context of P falciparum infection. (A) The speculative distribution of mature RBCs with different levels of splenic “crossability” at homeostasis. Approximately 1% of the circulating RBC population loses its ability to cross the spleen each day. When the spleen crossability of a RBC is below the splenic retention threshold, the corresponding RBC is retained in the cords of the red pulp. This retention is expected to trigger phagocytosis, followed by iron recycling into erythropoiesis. Aging of a RBC is associated with a progressive reduction of RBC deformability that influences RBC crossability. A link between deformability (assessed by ektacytometry) and spleen crossability has been established in thalassaemia. (B) 1. The elongation of ring-infected RBCs is reduced with a wide dispersion of individual values, as assessed using optical tweezers. Deformability values of rings span the splenic retention threshold, as shown by the retention of rings in an ex vivo human spleen-perfusion system. 2. The splenic crossability of a proportion of the ring population is therefore below the splenic retention threshold. This subpopulation is retained and (at least partially) phagocytosed, therefore unable to sequester in the vasculature of other organs. 3. The subpopulation that is still able to circulate is available for maturation and subsequent cytoadherence-based sequestration. Despite their gross inability to cross the spleen, cytoadherent mature forms are protected from splenic retention by sequestration in the microcirculation. 4. The biomass of sequestered mature forms generated at each cycle thus depends on the proportion of circulating rings and determines the number of rings produced at the next reinvasion wave. The proportion of rings allowed to circulate through the spleen is therefore a determinant of the in vivo multiplication factor of the parasite biomass. (C) Influence of a left shift in the crossability of RBCs. Several RBC disorders/polymorphisms are associated with a reduced RBC deformability or decreased ability of RBCs to cross the spleen (1). This abnormality may induce a similar shift in the deformability of ring-infected RBCs. The subpopulation of rings retained is therefore greater, and the subpopulation allowed to circulate until maturation and sequestration is smaller, giving rise to a smaller sequestered biomass of mature forms. The number of rings generated at the next reinvasion cycle is also smaller, leading to a reduced in vivo multiplication factor. This process may account for part of the protection from severe malaria induced by the HbAS trait (see text). (D) In an anemic condition, when a greater number of normal RBCs are retained in the spleen, the spleen clearance zone will be shifted to the right. If the splenicretention threshold is higher (1) (ie, the spleen retains RBCs with a higher crossability), the subpopulation of rings retained is greater (2), and the subpopulation allowed to circulate until maturation and sequestration is smaller (3), giving rise to a smaller sequestered biomass of mature forms. The number of rings generated at the next reinvasion cycle is also smaller, leading to a reduced in vivo multiplication factor. A more stringent spleen retention threshold also induces the retention of a greater proportion of normal RBCs, thereby favoring the occurrence of anemia. (E) Uninfected RBCs in the blood of patients or in culture usually have a reduced deformability (1). The population distribution curve of uninfected RBCs is therefore shifted to the left, a phenomenon predicted to increase the proportion of uninfected RBCs retained in the spleen, and thereby RBC loss and subacute/acute anemia. The existence of this third subpopulation of RBCs explains how anemia and a decrease of the deformability of circulating RBCs can be associated., Whether this process affecting uninfected RBCs is unimodal or multimodal is not known.
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