Evidence of promiscuous endothelial binding by
            <scp>
              <i>P</i>
            </scp>
            <i>lasmodium falciparum</i>
            ‐infected erythrocytes

Esser, Claudia; Bachmann, Anna; Kuhn, Daniela; Schuldt, Kathrin; Förster, Birgit; Thiel, Meike; May, Jürgen; Koch‐Nolte, Friedrich; Yáñez-Mó, Marı́a; Sánchez‐Madrid, Francisco; Schinkel, Alfred H.; Jalkanen, Sirpa; Craig, Alister G.; Bruchhaus, Iris; Horstmann, Rolf D.

doi:10.1111/cmi.12270

Cited by 23 publications

(21 citation statements)

References 51 publications

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“…Endothelial cytoadhesion and the binding capacities of various laboratory strains and patient isolates of P. falciparum have been mainly investigated under static conditions 6,31,32 . This is classically achieved by directly incubating IEs with cells or recombinant receptors of interest 8,16,33,34 . Finally, adherent IEs are counted manually.…”

Section: Resultsmentioning

confidence: 99%

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Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Lubiana

Bouws

Roth

et al. 2020

Sci Rep

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characterizing the adhesive dynamics of Plasmodium falciparum infected erythrocytes (IEs) to different endothelial cell receptors (ECRs) in flow is a big challenge considering available methods. This study investigated the adhesive dynamics of IEs to five ECRs (CD36, ICAM-1, P-selectin, CD9, CSA) using simulations of in vivo-like flow and febrile conditions. To characterize the interactions between ECRs and knobby and knobless IEs of two laboratory-adapted P. falciplarum isolates, cytoadhesion analysis over time was performed using a new tracking bioinformatics method. The results revealed that IEs performed rolling adhesion exclusively over CD36, but exhibited stationary binding to the other four ECRs. The absence of knobs affected rolling adhesion both with respect to the distance travelled by IEs and their velocity. Knobs played a critical role at febrile temperatures by stabilizing the binding interaction. Our results clearly underline the complexity of the IE-receptor interaction and the importance of knobs for the survival of the parasite at fever temperatures, and lead us to propose a new hypothesis that could open up new strategies for the treatment of malaria. Cytoadhesion of Plasmodium falciparum to human endothelial cell receptors (ECRs) causes complications and deaths following malaria infection. In 2018, 405,000 malaria-related deaths were registered (61% of which were of children younger than 5 years old) 1. Cytoadhesion leads to accumulation of infected erythrocytes (IEs) within the microvascular bed of vital organs such as the brain, lungs, and kidneys. Death can eventually occur due to decreased blood supply and organ failure 2,3. Cytoadhesion results from interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and different ECRs 4-8. About 60 var genes per parasite genome encode PfEMP1 family members. Only one PfEMP1 variant is located on the membrane of IEs at the trophozoite stage, but the corresponding var gene is already expressed at the ring stage in a mutually exclusive pattern 9. The most studied interaction partners are the ECRs CD36, intracellular adhesion molecule 1 (ICAM-1), endothelial protein C receptor, and chondroitin sulfate A (CSA) 6,7. In general, PfEMP1 molecules cluster on nanoscale protrusions, called knobs, located on the membrane of IEs. Knobs consist of various submembranous structural proteins, predominantly knob-associated histidine-rich protein (KAHRP) 10. KAHRP contains several binding domains that interact with both parasite and host factors. Knobs begin to appear on the surface of IEs at 16 h post-invasion (hpi). The density of knobs increases from 20 to 60/µm 2 with parasite development from the

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Section: Resultsmentioning

confidence: 99%

“…CHO-745 cells defective in glycosaminoglycan biosynthesis (American Type Culture Collection (ATCC); no. CRL-2242) were transfected and cultured as previously described 8,31,33 . CHO-745 cells transfected with GFP, CD36, ICAM-1, P-selectin, and CD9 were used.…”

Section: Discussionmentioning

confidence: 99%

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Lubiana

Bouws

Roth

et al. 2020

Sci Rep

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“…Additionally, a low constitutive expression of EPCR was observed particularly in the brain. These findings might serve as an explanation for the organ-specific pathology in CM, which is induced by cytoadherence of Plasmodium -infected red blood cells (iRBCs) in brain microvessels to a wide range of additional receptors [5] . It was suggested that a low capacity of EPCR to activate protein C caused by adherence of iRBCs and adjacent cleavage of EPCR could provoke a proinflammatory and procoagulant state in affected tissues.…”

Section: Introductionmentioning

confidence: 97%

Endothelial Protein C Receptor Gene Variants Not Associated with Severe Malaria in Ghanaian Children

et al. 2014

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BackgroundTwo recent reports have identified the Endothelial Protein C Receptor (EPCR) as a key molecule implicated in severe malaria pathology. First, it was shown that EPCR in the human microvasculature mediates sequestration of Plasmodium falciparum-infected erythrocytes. Second, microvascular thrombosis, one of the major processes causing cerebral malaria, was linked to a reduction in EPCR expression in cerebral endothelial layers. It was speculated that genetic variation affecting EPCR functionality could influence susceptibility to severe malaria phenotypes, rendering PROCR, the gene encoding EPCR, a promising candidate for an association study.MethodsHere, we performed an association study including high-resolution variant discovery of rare and frequent genetic variants in the PROCR gene. The study group, which previously has proven to be a valuable tool for studying the genetics of malaria, comprised 1,905 severe malaria cases aged 1–156 months and 1,866 apparently healthy children aged 2–161 months from the Ashanti Region in Ghana, West Africa, where malaria is highly endemic. Association of genetic variation with severe malaria phenotypes was examined on the basis of single variants, reconstructed haplotypes, and rare variant analyses.ResultsA total of 41 genetic variants were detected in regulatory and coding regions of PROCR, 17 of which were previously unknown genetic variants. In association tests, none of the single variants, haplotypes or rare variants showed evidence for an association with severe malaria, cerebral malaria, or severe malaria anemia.ConclusionHere we present the first analysis of genetic variation in the PROCR gene in the context of severe malaria in African subjects and show that genetic variation in the PROCR gene in our study population does not influence susceptibility to major severe malaria phenotypes.

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“…With many varied PfEMP1s in the genome, a major question has therefore been whether specific PfEMP1s, with specific receptor-binding phenotypes, are associated with particular severe disease syndromes. Indeed, PfEMP1 domains have been suggested to interact with a wide range of different human protein and carbohydrate ligands [24,25]. This raises several questions.…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Towards an anti-disease malaria vaccine

Lennartz

Lavstsen

Higgins

2017

Emerging Topics in Life Sciences

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Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

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Evidence of promiscuous endothelial binding by P lasmodium falciparum ‐infected erythrocytes

Cited by 23 publications

References 51 publications

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Endothelial Protein C Receptor Gene Variants Not Associated with Severe Malaria in Ghanaian Children

Towards an anti-disease malaria vaccine

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