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      Assessing the functional impact of PfRh5 genetic diversity on ex vivo erythrocyte invasion inhibition

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          Abstract

          The PfRh5-Basigin ligand–receptor interaction is an essential step in the merozoite invasion process and represents an attractive vaccine target. To reveal genotype–phenotype associations between naturally occurring allelic variants of PfRh5 and invasion inhibition, we performed ex vivo invasion inhibition assays with monoclonal antibodies targeting basigin coupled with PfRh5 next-generation amplicon sequencing. We found dose-dependent inhibition of invasion across all isolates tested, and no statistically significant difference in invasion inhibition for any single nucleotide polymorphisms. This study demonstrates that PfRh5 remains highly conserved and functionally essential, even in a highly endemic setting, supporting continued development as a strain-transcendent malaria vaccine target.

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          Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

          Magnus Manske, Olivo Miotto, Susana Campino … (2012)
          Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. 1,2 Here we describe methods for large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short term culture. Analysis of 86,158 exonic SNPs that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.
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            BASIGIN is a receptor essential for erythrocyte invasion by Plasmodium falciparum

            Cécile Crosnier, Leyla Bustamante, S Bartholdson … (2012)
            Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved 1-4 are required in all parasite strains suggesting that the parasite is able to access multiple redundant invasion pathways 5 . Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, BASIGIN, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth 6 . Erythrocyte invasion was potently inhibited by soluble BASIGIN or by BASIGIN knockdown, and invasion could be completely blocked using low concentrations of anti-BASIGIN antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a−) erythrocytes, which express a BASIGIN variant that has a weaker binding affinity for PfRh5, exhibited reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for novel anti-malarial therapies.
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              Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion.

              Subhash Singh, Anna Liu, L. Miller … (2008)
              Some human malaria Plasmodium falciparum parasites, but not others, also cause disease in Aotus monkeys. To identify the basis for this variation, we crossed two clones that differ in Aotus nancymaae virulence and mapped inherited traits of infectivity to erythrocyte invasion by linkage analysis. A major pathway of invasion was linked to polymorphisms in a putative erythrocyte binding protein, PfRH5, found in the apical region of merozoites. Polymorphisms of PfRH5 from the A. nancymaae-virulent parent transformed the nonvirulent parent to a virulent parasite. Conversely, replacements that removed these polymorphisms from PfRH5 converted a virulent progeny clone to a nonvirulent parasite. Further, a proteolytic fragment of PfRH5 from the infective parasites bound to A. nancymaae erythrocytes. Our results also suggest that PfRH5 is a parasite ligand for human infection, and that amino acid substitutions can cause its binding domain to recognize different human erythrocyte surface receptors.
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                Author and article information

                Contributors
                Amy K. Bei: amy.bei@yale.edu
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 26 January 2021
                Publication date PMC-release: 26 January 2021
                Publication date Collection: 2021
                Volume: 11
                Electronic Location Identifier: 2225
                Affiliations
                [1 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Epidemiology of Microbial Diseases, , Yale School of Public Health, ; New Haven, CT USA
                [2 ]GRID grid.418508.0, ISNI 0000 0001 1956 9596, G4-Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, , Institut Pasteur de Dakar, ; Dakar, Senegal
                [3 ]GRID grid.418508.0, ISNI 0000 0001 1956 9596, Pôle Virologie, Institut Pasteur de Dakar, ; Dakar, Senegal
                [4 ]Francis Crick African Network CAN Crick Fellow, London, UK
                Article
                Publisher ID: 81711
                DOI: 10.1038/s41598-021-81711-9
                PMC ID: 7838290
                PubMed ID: 33500482
                SO-VID: fa0feb9c-fdec-450f-a30c-21279bd8902e
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 6 October 2020
                Date accepted : 11 January 2021
                Funding
                Funded by: Wilbur Downs Fellowship
                Award ID: Wilbur Downs Fellowship
                Award Recipient :
                Funded by: Crick African Network Grant
                Award ID: CAN/B00002/1
                Award Recipient :
                Funded by: Institut Pasteur de Paris and Agence Universitaire de la Francophonie (AUF)
                Award ID: G45267
                Award Recipient :
                Funded by: Yale School of Public Health
                Award ID: Start-Up
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000061, Fogarty International Center;
                Award ID: K01 TW010496
                Award Recipient :
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Uncategorized
                Keywords: parasite biology,parasite genetics,parasite immune evasion
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: parasite biology, parasite genetics, parasite immune evasion

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