Reduced CD36-dependent tissue sequestration of <i>Plasmodium</i>-infected erythrocytes is detrimental to malaria parasite growth in vivo

Fonager, Jannik; Pasini, Erica M.; Braks, Joanna A. M.; Klop, Onny; Ramesar, Jai; Remarque, Edmond J.; Vroegrijk, Irene O.C.M.; Duinen, Sjoerd G. van; Thomas, Alan W.; Khan, Shahid M.; Mann, Matthias; Kocken, Clemens H. M.; Janse, Chris J.; Franke-Fayard, Blandine

doi:10.1084/jem.20110762

Cited by 105 publications

(208 citation statements)

References 61 publications

(128 reference statements)

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“…This alignment of clearance and sequestration suggests that parasite sequestration occurring earlier than is required to avoid clearance is of no great advantage to the parasite. This is surprising as other observations have suggested that parasite sequestration provides an even greater advantage to parasites than simply allowing them to escape clearance (15). Some investigators hypothesize that sequestration places parasites in favorable environments for asexual reproduction (38).…”

Section: Discussionmentioning

confidence: 92%

“…In addition, sequestration is partially associated with disease severity in P. falciparum infections, suggesting a possible causal link with high parasite biomass (14). Current in vivo modeling data are consistent with sequestration, providing a strong survival advantage to Plasmodium parasites (15,16). However, evidence that sequestration alone is sufficient to cause high parasite biomass is currently lacking.…”

mentioning

confidence: 84%

“…For simplicity, we set the clearance of sequestered parasites to zero [␦ T (x) ϭ 0]. This allows us to consider a system where the blood parasites are subject to much higher clearance than sequestered parasites since sequestration is generally regarded as a mechanism to avoid splenic clearance by the host (15,37,38). Parameter and functional choices for mathematical models.…”

Section: Methodsmentioning

confidence: 99%

“…RBCs infected with mature P. berghei ANKA parasites, specifically schizont stages, sequester effectively in the lungs of mice in a CD36-dependent manner (15). P. berghei ANKA-iRBCs also accumulate in large numbers in other organs, such as the spleen, liver, and brain, although parasite ligands required for this process have not been identified.…”

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confidence: 99%

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Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

et al. 2014

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Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizontspecific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. Malaria caused approximately 1,238,000 deaths worldwide in 2010 (1). Of the five different Plasmodium species that infect humans, Plasmodium falciparum is associated with greatest morbidity (2, 3). Parasite biomass and microvasculature obstruction are among the most reliable prognostic indicators in P. falciparum-infected humans, with high levels of either indicator being strongly associated with severe disease and negative outcome (4-6). High P. falciparum biomass could in theory result from poor clearance of freely circulating parasites by the host's mononuclear phagocytic system (MPS), principally macrophages in the spleen and liver. Clinical studies, including ex vivo perfusion of human spleens and analyses of splenectomized malaria patients, argue that humans can clear at least a proportion of circulating P. falciparum parasites (7-11). Furthermore, increased rigidity of red blood cells (RBCs) infected with P. falciparum parasites, particularly mature-stage trophozoites and schizonts, appears to render them less capable of passage through the spleen than either uninfected RBCs or ring-stage P. falciparum-infected RBCs (P. falciparum-iRBCs) (12). Thus, the human MPS can clear circulating mature P. falciparum-iRBCs, but its competency at doing so in vivo remains unclear. A mechanism that could facilitate increases in parasite biomass is evasion of the host MPS by sequestration of P. falciparum-iRBCs in peripheral tissues. A large body of literature has clearly identified P. falciparum-expressed ligands, which mediate adherence of schizont-and late-stage trophozoite-iRBCs to ...

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

et al. 2014

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“…The majority of sequestered parasites are found in the brain, lung, spleen, liver, kidney, small intestine, heart, and adipose tissue, as well as in the placenta in pregnancy-associated malaria (3,13,14). The microaerophilic venous environment of the deep microvessels nourishes the maturation of the parasites, facilitating their survival (15).…”

mentioning

confidence: 99%

Cytoadherence of Plasmodium berghei-Infected Red Blood Cells to Murine Brain and Lung Microvascular Endothelial CellsIn Vitro

et al. 2013

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dSequestration of infected red blood cells (iRBC) within the cerebral and pulmonary microvasculature is a hallmark of human cerebral malaria (hCM). The interaction between iRBC and the endothelium in hCM has been studied extensively and is linked to the severity of malaria. Experimental CM (eCM) caused by Plasmodium berghei ANKA reproduces most features of hCM, although the sequestration of RBC infected by P. berghei ANKA (PbA-iRBC) has not been completely delineated. The role of PbAiRBC sequestration in the severity of eCM is not well characterized. Using static and flow cytoadherence assays, we provide the first direct in vitro evidence for the binding of PbA-iRBC to murine brain and lung microvascular endothelial cells (MVEC). We found that basal PbA-iRBC cytoadherence to MVECs was significantly higher than that of normal red blood cells (NRBC) and of RBC infected with P. berghei K173 (PbK173-iRBC), a strain that causes noncerebral malaria (NCM). MVEC prestimulation with tumor necrosis factor (TNF) failed to promote any further significant increase in mixed-stage iRBC adherence. Interestingly, enrichment of the blood for mature parasites significantly increased PbA-iRBC binding to the MVECs prestimulated with TNF, while blockade of VCAM-1 reduced this adhesion. Our study provides evidence for the firm, flow-resistant binding to endothelial cells of iRBC from strain ANKA-infected mice, which develop CM, and for less binding of iRBC from strain K173-infected mice, which develop NCM. An understanding of P. berghei cytoadherence may help elucidate the importance of sequestration in the development of CM and aid the development of antibinding therapies to help reduce the burden of this syndrome.

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Plasmodium berghei ANKA (PbA) Infection of C57BL/6J Mice: A Model of Severe Malaria

Engwerda

Haque

2013

Mouse Models of Innate Immunity

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The term "severe malaria" refers to a wide spectrum of syndromes in Plasmodium-infected humans including cerebral malaria (CM), respiratory distress, severe anemia, liver dysfunction, and hypoglycemia. Mouse models have been employed to further our understanding of the pathology and immune responses that occur during Plasmodium infection. Evidence of brain, liver, lung, and spleen pathology, as well as anemia and tissue-sequestration of parasites, has been reported in various strains of inbred mice. While no single mouse model mimics all the various clinical manifestations of severe malaria in humans, here we describe a detailed protocol for Plasmodium berghei ANKA infection of C57BL/6J mice. For many years, this model has been referred to as "experimental cerebral malaria," but in fact recapitulates many of the symptoms and pathologies observed in most severe malaria syndromes.

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Reduced CD36-dependent tissue sequestration of Plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo

Abstract: P. berghei ANKA parasites deficient in schizont membrane-associated cytoadherence protein reveal a beneficial role for CD36-mediated tissue sequestration in aiding parasite growth.

Cited by 105 publications

References 61 publications

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

Cytoadherence of Plasmodium berghei-Infected Red Blood Cells to Murine Brain and Lung Microvascular Endothelial CellsIn Vitro

Plasmodium berghei ANKA (PbA) Infection of C57BL/6J Mice: A Model of Severe Malaria

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