Trends in Parasitology
ReviewPlasmodium vivax Infections of Duffy-Negative Erythrocytes: Historically Undetected or a Recent Adaptation?
Introduction
Plasmodium falciparum is the leading cause of death due to malaria around the world; Plasmodium vivax also causes severe disease in humans, predominantly in Asia and South America 1, 2, 3. The high death rate around the Thames estuary centuries ago was presumed to be caused by P. vivax [4]. P. vivax was thought to be absent in African populations who lack the Duffy blood group antigen (Duffy antigen) (see Glossary), that is, who are Duffy-negative. Recently, however, many cases of P. vivax infection in Duffy-negative populations have been reported in Angola, Benin, Botswana, Cameroon, Ethiopia, Equatorial Guinea, Kenya, Madagascar, Mali, Mauritania, Senegal, Sudan, and Uganda 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Among these new cases, infection has been observed to be less severe in Duffy-negative Africans than in Duffy blood group antigen positive (Duffy-positive) Africans. The concern is that mutations/evolution in P. vivax may put Duffy-negative Africans at risk of severe disease in the future.
The potential importance of P. vivax in Africa may be underestimated by leaders and policy makers. One reason for this could be the reporting of P. vivax infections, usually done on a case-by-case basis, rather than as a holistic map across Africa. In addition, because P. vivax may be asymptomatic, there is a need for PCR diagnostic tools to determine the true frequency of P. vivax throughout Africa. If P. vivax infections are not considered, P. vivax may hamper malaria control efforts and elimination in the future. Here, we summarize the existing evidence for P. vivax malaria in Duffy-negative Africans, highlight the P. vivax ligands and erythrocyte receptors involved in parasite-host interactions, and discuss possible avenues for culturing P. vivax, which will help in understanding parasite biology and support P. vivax elimination efforts.
Section snippets
Evidence for the Inability of P. vivax to Invade Duffy-Negative Erythrocytes
Malaria therapy for neurosyphilis was developed in 1919 by Julius Wagner-Jauregg. However, in 1932 P. vivax was found to be ineffective in treating African-Americans, who were thus deemed to be P. vivax-resistant [21]. Although a majority was resistant to P. vivax infection, resistance was not universal. Young et al. demonstrated that refractoriness was present after inoculation of P. vivax-infected blood, indicating that resistance was at the erythrocyte level [22]. Garnham described the
Plasmodium vivax in Duffy-Negative African Populations: A Recent Change?
Recently, P. vivax infection of Duffy-negative Africans has been observed in many parts of Africa (Figure 1 and Table 1) and in South America where Duffy-negative people of African origin live 5, 6, 7, 8, 9, 10, 11, 15, 19, 28, 29, 30. P. vivax infections have also recently been observed in Senegal, Botswana, and Uganda, but the Duffy antigen status in these cases was not determined 12, 16, 18, 31. The first report of P. vivax infection in Duffy-negative Africans was from Kenya [5]. It is of
Merozoite–Erythrocyte Interactions
In 1995, the molecular basis for Duffy negativity was identified as a single point mutation in the binding site for GATA1, an erythroid transcription factor that binds upstream of the Duffy antigen coding region [34]. Because of the mutation, erythrocytes do not express the Duffy antigen on their surface – hence their refractoriness to P. vivax and P. knowlesi infection 24, 25. The P. vivax ligands responsible for invasion of Duffy-negative erythrocytes are not known. Multiple ligands are found
Duffy Antigen Exposure to P. vivax on Erythrocytes
Interestingly, DBP1 region II, expressed on COS cell surfaces, has been shown to bind to all aged erythrocytes [41]. Significantly, Choe et al. found that tyrosine 41 sulfation in the N-terminal region of Duffy antigen is critical for the binding of DBP1 to erythrocytes [45]. The binding of COS cells expressing DBP-1 to erythrocytes was blocked by the wild-type Duffy antigen sequence, but not by a mutated sequence (tyrosine 41 to phenylalanine) that lacked sulfation of tyrosine 41 [45].
Another Ligand of the Duffy Family
The de novo genome assembly of a P. vivax isolate from Cambodia led to the identification of erythrocyte-binding protein (EBP/DBP2), which has a conserved Duffy binding-like domain and C-terminal cysteine-rich domain before the transmembrane domain [49]. The Duffy-binding domain of EBP binds to both Duffy-positive and Duffy-negative erythrocytes at a very low level [14]. However, a study by Ntumngia et al. showed that EBP/DBP2 binds preferentially to young/immature CD71 high reticulocytes [50] (
RBPs of P. vivax
A second family of proteins involved in P. vivax erythrocyte invasion consists of the RBPs (Table 2) that were first discovered in Plasmodium yoelii [51]. Two proteins (PvRBP1a and PvRBP2c) were identified in a λgt11 P. vivax cDNA expression library that bound to reticulocytes [52]. The RBP family contains five reticulocyte homology (RH) genes in P. falciparum [53]. With the completed P. vivax genome sequences, 11 P. vivax -RBP genes have been identified 49, 54. Unlike the DBP genes localized
Other Potential Ligands of P. vivax
Other genes, such as glycophosphatidylinositol-anchored micronemal antigen (GAMA) and tryptophan-rich antigens, may be responsible for the low-density P. vivax invasion of Duffy-negative erythrocytes (Table 2). Like P. falciparum, GAMA is also localized in the micronemes of the P. vivax merozoites and has been shown to bind to Duffy-negative erythrocytes, and more recently has been shown to bind more efficiently to CD71hi immature reticulocytes than to mature erythrocytes 59, 60. The
Concluding Remarks and Future Perspectives
Technical advancements in diagnostics have improved markedly in the past few decades. Such advancements may account for the recent detection of low-density P. vivax in Africans, which appears to have been originally missed. Although, P. vivax infection in Africa is low density, P. vivax can cause malarial disease in Duffy-negative populations. Some of the reported cases of P. vivax in Africa were symptomatic 6, 10, with some possibly inducing anemia 5, 20. However, we cannot rule out the
Acknowledgments
This work was supported by the Intramural Research Program of the Division of Intramural Research and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. We thank DELTAS Africa Initiative Grant # DEL-15-010 for the support of training through the Malaria Research Capacity Development in West and Central Africa and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, USA, for Award Number R01AI099628 supporting
Glossary
- COS cell
- a mammalian fibroblast-like cell line which expresses the parasite ligand on its surface for binding erythrocytes.
- DBP1 copy number expansion
- Duffy-binding protein 1 (DBP1) copy number expansion may play a role in P. vivax invasion of Duffy-negative erythrocytes, although duplication also occurs in countries (e.g., southeast Asia) where Duffy negativity does not occur.
- Duffy blood group antigen (Duffy antigen)
- Duffy blood group antigen is a protein that is expressed on the surface of the
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