Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature.

Michael Dörpinghaus,Finn Fürstenwerth,Philip Bouws,Paolo Mesén-Ramírez,Stephan Lorenzen,Lisa K Roth,Iris Bruchhaus,Vincent Jordan,Anna Bachmann,Katharina Höhn,Nahla Galal Metwally,Maximilian Rakotonirinalalao,Eva Pansegrau,Thomas Roeder,Michaela Sauer,Torben Rehn

doi:10.3390/microorganisms8020174

Michael Dörpinghaus, Finn Fürstenwerth + Show 14 more

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https://doi.org/10.3390/microorganisms8020174

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Abstract

Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.

Highlights

After decades of research, malaria remains a major public health burden
Cytoadhesion of Infected Erythrocytes to HBEC-5i Cells Was Mediated by VAR2CSA
The present study revealed the impact of febrile temperature on the binding phenotype of P. falciparum infected erythrocytes (IEs) to chondroitin-4-sulfate A (CSA) on immortalized HBEC-5i human brain endothelial cells, as well as intercellular adhesion molecule 1 (ICAM-1) and CD3N6oerxmpaolsizeeddoEnxptrraensssigoennLicevCeHl O ceNllso.rmalized Expression Level oICCfRAcLGeM-rHe3ep-n2kBb1feea4,Ermh5NaVCrpTMlpaC3-em)5A.niedMcTeohl-tl1ehsPP,FFewpaGIIlnrTTieaeed__rslne00eVec22dne00EIetl11D-lr32cssi00a.tv00udePdhdryeiforrCidronHemIs,mTOtCu4a2IoS5CId4Ch6AAn1AiMuesMc-tsm1-(ra14maen0ast°RneataNdlcsbeAotlCrhi)ebsHabhIetTOreda14edC2l.eCn3DtDct3reo36hi64ccra0tthet°emdxinoeaInnanTdtd00t4hd,oNetEifhtsiIeouErCnresfHfatoIooTcOnr(ee4RsI0C,IH0oeC.NA3eAvfMExAMHe-hB1-sr13iEeaC7bqlB°i-)tr5Cee*i-dcC5ceimeHpIclTOltaeso44jlC2olrC4pDsrsD3r(36fos6A3eu7daT°cutCuhcCreaed®ss a parasviatre01populaPtiFoITn_m06a1i6n5l0y0 express1in0g7 var2csa, wh1ic.6h encode6s8VAR2CS5A59,1t1he binding17p0artner of CSA [v7a,r82,c4s7a]

Summary

Introduction

Malaria is a tropical disease caused by five different human pathogenic Plasmodium species, of which P. falciparum is the most deadly. The infection can lead to seizures, coma, and death [1]. These clinical symptoms are related to the life cycle of the parasite. During its life cycle in the human host, the parasite invades erythrocytes. The infected erythrocytes (IEs) adhere to endothelial cells, which obstructs blood flow in microvessels. This can lead to hypoxia, induction of the inflammatory response, tissue damage, and organ failure [2,3]

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