Transferrin receptor 1 is a reticulocyte-specific receptor for
            <i>Plasmodium vivax</i>

Gruszczyk, Jakub; Kanjee, Usheer; Chan, Li‐Jin; Menant, Sébastien; Malleret, Benoît; Lim, Nicholas; Schmidt, Christoph Q.; Mok, Yee Foong; Lin, Kai-Min; Pearson, Richard D.; Rangel, Gabriel W.; Smith, Brian J.; Call, Melissa; Weekes, Michael P.; Griffin, Michael D. W.; Murphy, James M.; Abraham, Jonathan; Sriprawat, Kanlaya; Menezes, Marcelo Bezerra de; Ferreira, Marcelo U.; Russell, Bruce; Rénia, Laurent; Duraisingh, Manoj T.; Tham, Wai‐Hong

doi:10.1126/science.aan1078

Cited by 178 publications

(262 citation statements)

References 82 publications

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“…Table 2 and Table S2 show the individual ranking of all 60 proteins by AUC, note that it is not necessarily the proteins with the highest individual AUC that work best in combination. Table 2, for the top protein PVX_094255 (RBP2b), there were two protein constructs, mapping to different regions of the protein (RBP2b 161-1454 and RBP2b 1986-2653 ), produced in two separate laboratories using different expression and purification methods (30,36). Antibody levels to the two constructs of PVX_094255 (RBP2b 161-1454 and RBP2b 1986-2653 ) were highly correlated (spearman r=0·72, p<0·0001, all cohorts combined) and for this reason the construct that provided lower levels of classification accuracy (region encompassing aa1986-2653) was excluded from the top eight in order to increase the information content provided.…”

Section: Validation Phasementioning

confidence: 99%

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Longley

Takashima

et al. 2018

Preprint

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One Sentence Summary: The manuscript describes identification and validation of a novel panel of P. vivax proteins that can be used to detect recent exposure to P. vivax infections within the prior 9 months.Abstract: In order to accelerate towards malaria elimination, improved targeting of limited resources is essential. A major gap in our elimination toolkit for Plasmodium vivax malaria is the identification of individuals carrying arrested liver stages, called hypnozoites. These clinically silent but frequently relapsing hypnozoites are key to P. vivax persistence. Whilst hypnozoites cannot be directly detected, individuals who have had recent exposure to P. vivax and have not been treated are likely to harbor these parasites. By measuring IgG antibody responses to over 300 P. vivax proteins, a panel of serological markers capable of detecting exposure to P. vivax infections in the prior 9-month period was identified and validated. Using antibody responses to 8 P. vivax proteins, 80% sensitivity and specificity for detecting recent infections were achieved in three independent studies conducted in Thailand, Brazil and the Solomon Islands. As these individuals have a high likelihood of harboring hypnozoites, the suite of these 8 antibody responses can serve as biomarkers for the identification of individuals who should be targeted for treatment with liver-stage drugs such as primaquine and tafenoquine in mass drug administration programs aimed at controlling and eliminating P. vivax malaria. [Main Text: ]

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Section: Validation Phasementioning

confidence: 99%

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Longley

Takashima

et al. 2018

Preprint

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“…Given a wide range of results pointing to P. vivax preference for infection of reticulocytes (40-48) and the apparent low, variable expression Fy protein on Fy*B ES /*B ES pbRBC, we postulated that this expression pattern may reflect the lower and declining stages of Fy expression on aging pbRBC. Further recent evidence from murine studies showing that the Fy protein is expressed at higher levels on pro-erythroblasts and normoblasts, compared to mature RBC (49), suggesting that we should investigated Fy expression in erythroid precursors.…”

Section: Resultsmentioning

confidence: 99%

“…Our initial studies focused on peripheral blood RBCs (pbRBC), showed that Fy expression on Fy-negative pbRBC was periodically positive and that these RBC could interact with rPvDBPII at levels similar to RBC from FY*A/*A people. Well aware that numerous studies point to P. vivax preference for infection of reticulocytes (40, 42-48), we were interested to study Fy expression across a broader time frame of erythroid development. Recent evidence from murine and human studies shows higher levels of Fy protein expression on pro-erythroblasts and normoblasts, compared to mature RBC (46, 49).…”

Section: Discussionmentioning

confidence: 99%

Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals

Dechavanne

Métral

et al. 2018

Preprint

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Tel : +33 (0)1 44 49 31 47 (Dial 0 only within France) SignificanceDuffy blood group negativity results from a single nucleotide polymorphism (SNP) in the gene promoter, and reaches genetic fixation in many African ethnicities. Because the Duffy protein (Fy) is an important contact point during Plasmodium vivax human red blood cell invasion, Fy-negativity is considered to confer resistance to P. vivax malaria.With recent studies in African countries reporting P. vivax infection in Fy-negative people, we studied Fy expression across erythroid development. Here we report that the FY promoter SNP does not abolish Fy protein expression in erythroid progenitors developing in the bone marrow. These results further emphasizes the importance of reticulocytes as targets for P. vivax blood stage infection and propose a mechanism for P. vivax infections in Fy-negative people. Abstract The gene encoding the Duffy blood group protein (Fy, CD234; additional designations Duffy Antigen Receptor of Chemokines [DARC] and Atypical Chemokine Receptor 1 [ACKR1]) is characterized by a SNP in a GATA-1 transcription factor binding site associated with the erythrocyte silent (ES) phenotype. FY ES homozygous people are viewed to be highly resistant to blood stage infection with Plasmodium vivax. Increasingly, however, studies are reporting P.vivax infections in Fy-negative individuals across malarious African countries where FY ES approaches genetic fixation. This suggests that P. vivax has evolved a Fy-independent RBC invasion pathway, or that the GATA-1 SNP does not abolish Fy expression. Here, we tested the second hypothesis through binding studies to erythroid lineage cells using recombinant P. vivax Duffy binding protein, the parasite's invasion ligand and Fy6-specific antibodies. We first observed variable Fy expression on circulating RBCs, irrespective of FY genotype; FY ES RBCs were periodically Fy-positive. Furthermore, during the in vitro erythroid differentiation of CD34+ cells and on ex vivo bone marrow samples, we observed Fy expression on erythroid precursor cells from FY ES people. Finally, the Fy6-specific nanobody, CA111 was used to capture Fy from the surface of FY ES RBCs. Our findings reveal that the GATA-1 SNP does not fully abolish Fy expression and provide insight on potential susceptibility of Fy-negative people to vivax malaria.

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“…Here we show that transgenic P. knowlesi parasites using PvDBP for invasion have no such restriction, invading human RBCs (which typically contain less than 0.5% reticulocytes) with the same efficiency as those expressing PkDBP – thus providing compelling evidence that PvDBP plays no role in the reticulocyte tropism. Further, recent work determining that PvRBP2b, which lacks an orthologue in P. knowlesi , binds to the reticulocyte specific marker CD71 (50) further asserts the RBPs as the key to reticulocyte tropism. Importantly, the ability to compare and contrast activity of Pk/Pv DBP family members in parasitological assays will provide a vital new tool to test hypotheses and models arising from studies that have until now relied on assays using recombinant protein fragments.…”

Section: Discussionmentioning

confidence: 99%

Rapid and iterative genome editing in the zoonotic malaria parasitePlasmodium knowlesi: New tools forP. vivaxresearch

Mohring

Hart

Rawlinson

et al. 2019

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19Tackling relapsing Plasmodium vivax and zoonotic Plasmodium knowlesi infections is critical to 20 reducing malaria incidence and mortality worldwide. Understanding the biology of these important and 21 related parasites was previously constrained by the lack of robust molecular and genetic approaches. 22Here, we establish CRISPR-Cas9 genome editing in a culture-adapted P. knowlesi strain and define 23 parameters for optimal homology-driven repair. We establish a scalable protocol for the production of 24 repair templates by PCR and demonstrate the flexibility of the system by tagging proteins with distinct 25 cellular localisations. Using iterative rounds of genome-editing we generate a transgenic line expressing 26 P. vivax Duffy binding protein (PvDBP), a lead vaccine candidate. We demonstrate that PvDBP plays 27 no role in reticulocyte restriction but can alter the macaque/human host cell tropism of P. knowlesi. 28Critically, antibodies raised against the P. vivax antigen potently inhibit proliferation of this strain, 29providing an invaluable tool to support vaccine development. 30 31 32 33 Main Text: 34 Introduction: 35Malaria remains a serious health burden globally, with over 216 million cases annually (1). Plasmodium 36 falciparum is responsible for 99 % of estimated malaria cases in sub-Saharan Africa. Outside Africa, P. 37 vivax is the predominant parasite and causes ~7.4 million clinical cases annually (1). Despite extensive 38 efforts, in 2016 the number of malaria cases were on the rise again for the first time in several years. 39Achieving global malaria eradication requires new tools and approaches for addressing emerging drug 40 resistance, relapsing P. vivax infections, and emerging zoonotic P. knowlesi infections, which represent 41 significant causes of severe disease and death (2). 42Although P. vivax displays some distinctive features to P. knowlesi, including the formation of latent 43 hypnozoites stages in the liver and restriction to reticulocytes in the blood (3), the two parasites are 44 closely related, occupying a separate simian parasite clade to P. falciparum (4) Host cell invasion by P. 45 vivax and P. knowlesi relies on the Duffy binding proteins (DBP) PvDBP and PkDBPα, respectively, 46 both ligands for human red blood cell (RBC) Duffy antigen/receptor for chemokines (DARC) (5-8). 47The critical binding motif of the ligands is the cysteine-rich region 2 (DBP-RII), with ~70 % identity 48 between PkDBPα and PvDBP (9). Despite their similarity, PvDBP has also been implicated in both P. 49 vivax reticulocyte restriction (10) and as a host tropism factor preventing P. vivax from infecting 50 macaques (11). PvDBP-RII is also the leading blood stage vaccine candidate for P. vivax (12-14), with 51 antibodies targeting PvDBP-RII blocking parasite invasion in ex vivo P. vivax assays (15). P. knowlesi 52 additionally contains two PkDBPα paralogues, namely DBPβ and DBPγ which share high levels of 53 amino acid identity (68-88 %) to PkDBPα but bind to distinct receptors via N-glycolylneuramin...

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Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax

Cited by 178 publications

References 82 publications

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Development and validation of serological markers for detecting recent exposure toPlasmodium vivaxinfection

Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals

Rapid and iterative genome editing in the zoonotic malaria parasitePlasmodium knowlesi: New tools forP. vivaxresearch

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