PfEMP1 expression is reduced on the surface of knobless<i>Plasmodium falciparum</i>infected erythrocytes

Horrocks, Paul; Pinches, Robert; Chakravorty, Srabasti J.; Papakrivos, Janni; Christodoulou, Zóe; Kyes, Susan; Urban, Britta C.; Ferguson, David J. P.; Newbold, Chris

doi:10.1242/jcs.02381

Cited by 76 publications

(96 citation statements)

References 49 publications

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“…However, a circular zone of clearing is also evident around the edges of the knob protrusions, similar to what was seen previously by low-resolution freeze-fracture SEM of the P-face ( Figure 7B). 19,39 These findings demonstrate that the knob membrane has a distinct distribution of membrane proteins from the surrounding erythrocyte membrane, including a discrete structure at the apex.…”

Section: Membrane Proteins Are Reorganized At Knobsmentioning

confidence: 94%

“…[18][19][20] KAHRP is localized with PfEMP1 in knobs, 18,21 where it has been shown by immuno-EM to be associated with an electron-dense (as visualized in heavy metal-stained specimens) layer of material under the membrane, as well as in Maurer's clefts. 22,23 KAHRP is a 59-72 kDa protein (550-657 amino acid residues depending on the variant) containing an N-terminal signal sequence and a PEXEL (Plasmodium export element) motif that mediate export into the erythrocyte, a 63-amino acid histidine-rich (55%) region, and 2 variable tandem repeat regions.…”

Section: Introductionmentioning

confidence: 99%

“…15,16 Loss of the ability to form erythrocyte knobs has been linked with a loss of parasite virulence in primate infections, 17 and with reduced cytoadherence in vitro. 15,18,19 The formation of the PfEMP1-presenting knobs is dependent on the expression of the parasite-derived knob-associated histidine-rich protein (KAHRP). Erythrocytes infected with KAHRP-negative P falciparum lack knobs and show diminished PfEMP1 presentation The online version of this article contains a data supplement.…”

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confidence: 99%

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A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes

Watermeyer

Hale

Hackett

et al. 2016

Blood

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Key Points• Plasmodium falciparumgenerated cytoadherent knobs on infected erythrocytes contain a spiral framework linked to the red cell cytoskeleton.• The findings suggest a structural basis for transmission of shear forces in adhesion of infected cells.Much of the virulence of Plasmodium falciparum malaria is caused by cytoadherence of infected erythrocytes, which promotes parasite survival by preventing clearance in the spleen. Adherence is mediated by membrane protrusions known as knobs, whose formation depends on the parasite-derived, knob-associated histidine-rich protein (KAHRP). Knobs are required for cytoadherence under flow conditions, and they contain both KAHRP and the parasite-derived erythrocyte membrane protein PfEMP1. Using electron tomography, we have examined the 3-dimensional structure of knobs in detergent-insoluble skeletons of P falciparum 3D7 schizonts. We describe a highly organized knob skeleton composed of a spiral structure coated by an electron-dense layer underlying the knob membrane. This knob skeleton is connected by multiple links to the erythrocyte cytoskeleton. We used immuno-electron microscopy (EM) to locate KAHRP in these structures. The arrangement of membrane proteins in the knobs, visualized by high-resolution freeze-fracture scanning EM, is distinct from that in the surrounding erythrocyte membrane, with a structure at the apex that likely represents the adhesion site. Thus, erythrocyte knobs in P falciparum infection contain a highly organized skeleton structure underlying a specialized region of membrane. We propose that the spiral and dense coat organize the cytoadherence structures in the knob, and anchor them into the erythrocyte cytoskeleton. The high density of knobs and their extensive mechanical linkage suggest an explanation for the rigidification of the cytoskeleton in infected cells, and for the transmission to the cytoskeleton of shear forces experienced by adhering cells. (Blood. 2016;127(3):343-351) IntroductionPlasmodium falciparum malaria remains one of the leading causes of child deaths globally, with the majority of cases occurring in subSaharan Africa and Southeast Asia. Although chemopreventive and vector control initiatives led to an estimated 42% reduction in mortality rates between 2000 and 2012, the emergence of artemisinin resistance highlights the importance of continued efforts to understand and interfere with the biology of the parasite. 1Of the 5 Plasmodium species capable of infecting humans, P falciparum and P vivax are the most prevalent, with P falciparum causing 90% of malaria-related deaths. P falciparum-infected erythrocytes become cytoadherent, causing erythrocyte sequestration in the microvasculature and avoiding clearance of infected cells by the spleen.2 Much of the virulence of P falciparum malaria has been attributed to this cytoadherence, which impedes blood circulation and results in severe syndromes such as cerebral or placental malaria. 2-4The dominant ligand mediating cytoadherence is PfEMP1, a major variable erythrocyte...

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Section: Membrane Proteins Are Reorganized At Knobsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes

Watermeyer

Hale

Hackett

et al. 2016

Blood

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“…Truncation of the kahrp gene, that encodes KAHRP, leads to development of knobless IEs. Knobless IEs are known to Onyambu et al 17 have reduced ability to bind to purified receptors compared to knobbed IEs (Horrocks et al, 2005). Recent published data has shown that clumping parasites can be selected from knobless parasite line DD2 (Arman et al, 2013).…”

Section: Mechanisms For Platelet-mediated Clumpingmentioning

confidence: 99%

Platelet-mediated clumping adhesion phenotypes of P. falciparum-infected erythrocytes: A review

Onyambu¹,

Tanui²,

Alwala³

et al. 2017

Clin. Rev. Opinions

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Malaria is a leading cause of morbidity and mortality in the world. In general, malaria is easily treated but in a subset of cases it develops to severe disease. Severe malaria has a high rate of mortality even with the best available care. This creates the need for intensive research to fully characterise the pathogenesis of the disease in order to create future novel therapies. One of the hallmarks of malaria infections is its ability to adhere to specific sites in the body leading to severe disease syndromes such as cerebral malaria and pregnancy associated malaria. In this review, the platelet-mediated clumping adhesion phenotypes of malaria-infected erythrocytes were discussed in the context of infected erythrocyte adhesion phenotypes such as cytoadhesion and rosetting. Platelet-mediated clumping refers to a phenomenon of P. falciparum-infected erythrocytes whereby they agglutinate to form large aggregates held together by activated platelets. This unique phenotype is important because it has been associated with severe malaria in both children and adults in diverse geographical and transmission settings. The precise mechanisms by which platelet-mediated clumping occurs are yet to be precisely described. The platelet receptors implicated in this phenotype include CD36, P-Selectin and gC1qR. The parasite derived ligands that mediate this phenotype are yet to be described.

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“…This pfEMP-1 is a key virulent factor for Plasmodium falciparum infection. This protein is expressed on the surface of infected erythrocytes and directly mediates adhesion to a variety of host cells [12].…”

Section: Cellular Adaptationsmentioning

confidence: 99%

Protection Against Malaria in Man: a Probe into some of the Implicated Mechanisms in Sub-Saharan Africa

Chiabi¹,

Obadeyi²,

Mbassi³

et al. 2013

TOARSJ

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Abstract:Malaria is amongst the most common parasitic infections in the world. In Africa it causes one in every five childhood deaths, with one child dying of malaria every 30 seconds. People living in malaria endemic areas appear to have protective immune mechanisms, which may be naturally occurring or acquired from exposure to the malaria parasite. These protective factors play an important role in reducing morbidity and mortality from malaria. This review is aimed at exploring and explaining the mechanisms for a selection of the main protective factors to malaria in man. Using an extensive literature review of prominent articles, this paper identifies and summarizes these mechanisms which may be acquired or genetic. The challenge for the future will be to translate these notions into the development of interventions for the prevention and treatment of malaria.

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PfEMP1 expression is reduced on the surface of knoblessPlasmodium falciparuminfected erythrocytes

Abstract: . (1995). Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes.

Cited by 76 publications

References 49 publications

A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes

A spiral scaffold underlies cytoadherent knobs in Plasmodium falciparum–infected erythrocytes

Platelet-mediated clumping adhesion phenotypes of P. falciparum-infected erythrocytes: A review

Protection Against Malaria in Man: a Probe into some of the Implicated Mechanisms in Sub-Saharan Africa

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