Malaria Parasite Ligands And Host Cell Receptors

National Institute Of Allergy And Infectious Diseases

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Abstract

Accomplishments during the year: 1. Cytoadhesion of Plasmodium falciparum-infected erythrocytes (IEs) to the endothelial lining of blood vessels protects parasites from splenic destruction, but also leads to detrimental inflammation and vessel occlusion. Surface display of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands exposes them to host antibodies and serum proteins. PfEMP1 are important targets of acquired immunity to malaria, and through evolution, the protein family has expanded and diversified to bind a select set of host receptors through antigenically diversified receptor-binding domains. Here, we show that complement component 1s (C1s) in serum cleaves PfEMP1 at semiconserved arginine motifs located at interdomain regions between the receptor-binding domains, rendering the IE incapable of binding the two main PfEMP1 receptors, CD36 and endothelial protein C receptor (EPCR). Bioinformatic analyses of PfEMP1 protein sequences from 15 P. falciparum genomes found the C1s motif was present in most PfEMP1 variants. Prediction of C1s cleavage and loss of binding to endothelial receptors was further corroborated by testing of several different parasite lines. These observations suggest that the parasites have maintained susceptibility for cleavage by the serine protease, C1s, and provides evidence for a complex relationship between the complement system and the P. falciparum cytoadhesion virulence determinant. "Complement C1s cleaves PfEMP1 at interdomain conserved sites inhibiting Plasmodium falciparum cytoadherence.Yvonne Azasi, Leanne M Low, Ashley N Just, Sai S R Raghavan, Christian W Wang, Paola Valenzuela-Leon, J Alexandra Rowe, Joseph D Smith, Thomas Lavstsen, Louise Turner, Eric Calvo, Louis H Miller. Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):e2104166118. doi: 10.1073/pnas.2104166118." 2. The Duffy blood group is a critical receptor for Plasmodium vivax (P. vivax) invasion of red blood cells, and consequently, P. vivax infections were considered rare in sub-Saharan Africa where the prevalence of Duffy-negativity is high. However, recently, P. vivax infections have been found in Duffy-negative Africans throughout the malaria transmission area of sub-Saharan Africa, raising important questions concerning the molecular composition of these P. vivax clones and the red blood cell receptors that facilitate their invasion. Here, we describe an unusually high number of P. vivax infections in febrile Duffy-negative Africans in Dschang, Cameroon (177 of 500 outpatients), as compared with Santchou (two of 400 outpatients) and Ky-ossi (two of 101 outpatients), in other areas in Cameroon. In the discussion, we speculate on the possible reasons why Dschang might account for the unusually large numbers of P. vivax infections in Duffy-negative individuals living there. "Plasmodium vivax Infections Detected in a Large Number of Febrile Duffy-Negative Africans in Dschang, Cameroon. Ghyslaine Bruna Djeunang Dongho, Karthigayan Gunalan, Mariangela L'Episcopia, Giacomo Maria Paganotti, Michela Menegon, Rose Efeutmecheh Sangong, Georges Bouting Mayaka, Joseph Fondop, Carlo Severini, Martin Sanou Sobze, Louis H Miller , Gianluca Russo.Am J Trop Med Hyg. 2021 Jan 12;104(3):987-992. doi: 10.4269/ajtmh.20-1255."