Plasmodium vivax Invasion of Human Erythrocytes Inhibited by Antibodies Directed against the Duffy Binding Protein

18 Dec 2007

Source: PLoS Medicine (see original article or PDF)

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Citation: Grimberg BT, Udomsangpetch R, Xainli J, McHenry A, Panichakul T, et al. (2007) Plasmodium vivax invasion of human erythrocytes inhibited by antibodies directed against the duffy binding protein. PLoS Med 4(12): e337. doi:10.1371/journal.pmed.0040337

Editors' Summary

Background.

Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Four different parasites cause malaria—the commonest and most widely distributed of these is Plasmodium vivax. Infections with P. vivax are rarely fatal, but they cause debilitating chills and fevers that recur every other day if untreated. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a form of the parasite known as sporozoites into people. The sporozoites replicate inside liver cells without causing any symptoms. Then, 8–9 d later, merozoites (another form of the parasite) are released from the liver cells and invade young red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. The characteristic symptoms of malaria are caused by this cyclical increase in the parasite burden. P. vivax infections are usually treated with chloroquine, but patients must also take a second drug called primaquine. This drug kills hypnozoites, a form of the parasite that hibernates in the liver and that can cause a relapse many months after the initial bout of malaria.

Why Was This Study Done?

P. vivax is becoming resistant to chloroquine and, although other antimalarial drugs still kill it, a vaccine that would limit the severity of P. vivax infections by blocking its ability to invade red blood cells is urgently needed. The invasion of red blood cells by P. vivax depends on an interaction between the Duffy antigen (a protein on the surface of human red blood cells) and the Duffy binding protein (PvDBP), which is expressed by merozoites. People who lack the Duffy antigen are resistant to blood-stage infections of P. vivax. Similarly, people who express half the normal amount of Duffy antigen on their red blood cells have reduced susceptibility to these infections. In this study, the researchers investigated whether antibodies (proteins made by the immune system that recognize foreign proteins) directed against PvDBP inhibit the invasion of human red blood cells by P. vivax.

What Did the Researchers Do and Find?

The researchers injected a fragment of PvDBP called PvDBPII into rabbits and purified the part of the blood that contains antibodies from the animals. They also isolated antibodies to PvDBPII from the blood of several Papua New Guineans who had been exposed to P. vivax. Both types of antibodies bound to PvDBPII in test tubes and to PvDBP expressed on P. vivax merozoites. Then, the researchers showed that both types of antibody inhibited the binding of PvDBPII to Duffy antigen when the antigen was in solution and when it was present on human red blood cells. Finally, to test the ability of the antibodies to inhibit red blood cell invasion by P. vivax, the researchers established short-term cultures of the parasite from blood taken from infected adults living in Thailand. Addition of the rabbit or human antibodies to these cultures inhibited parasite invasion of red blood cells by more than 50%.

What Do These Findings Mean?

These findings show, for what is believed to be the first time, that antibodies recognizing a fragment of PvDBP can partly inhibit the invasion of red blood cells by P. vivax merozoites. The results with the human antibodies are particularly important as they strongly suggest that a PvDBP-based vaccine might provide protection against blood-stage P. vivax infections. Whether the level of inhibition of invasion seen in this study will be sufficient to reduce the clinical severity of these infections will only become clear, however, when a vaccine is tested in people. The findings also indicate that short-term P. vivax cultures can be used to test whether antibodies that recognize other merozoite proteins also inhibit invasion. Unlike P. falciparum (the other major malarial parasite), P. vivax cannot be grown continuously in the laboratory. These short-term cultures will at last provide vaccine developers with a way to evaluate antigens as candidates for inclusion in P. vivax vaccines.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040337.

MedlinePlus encyclopedia page on malaria (in English and Spanish)
Information from the US Centers for Disease Control and Prevention on malaria (in English and Spanish)
Vivaxmalaria, information for the malaria research community on topics related to Plasmodium vivax
Information from the Malaria Vaccine Initiative about malaria and malaria vaccines, including a fact sheet on Plasmodium vivax malaria

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Source

Title:
Plasmodium vivax invasion of human erythrocytes inhibited by antibodies directed against the Duffy binding protein.

Authors:
Grimberg BT, Udomsangpetch R, Xainli J, McHenry A, Panichakul T, Sattabongkot J, Cui L, Bockarie M, Chitnis C, Adams J, Zimmerman PA, King CL

References:
PLoS Med. Dec 2007: Vol. 4 no. 12, pp. e337

Abstract:
Plasmodium vivax invasion requires interaction between the human Duffy antigen on the surface of erythrocytes and the P. vivax Duffy binding protein (PvDBP) expressed by the parasite. Given that Duffy-negative individuals are resistant and that Duffy-negative heterozygotes show reduced susceptibility to blood-stage infection, we hypothesized that antibodies directed against region two of P. vivax Duffy binding protein (PvDBPII) would inhibit P. vivax invasion of human erythrocytes.Using a recombinant region two of the P. vivax Duffy binding protein (rPvDBPII), polyclonal antibodies were generated from immunized rabbits and affinity purified from the pooled sera of 14 P. vivax-exposed Papua New Guineans. It was determined by ELISA and by flow cytometry, respectively, that both rabbit and human antibodies inhibited binding of rPvDBPII to the Duffy antigen N-terminal region and to Duffy-positive human erythrocytes. Additionally, using immunofluorescent microscopy, the antibodies were shown to attach to native PvDBP on the apical end of the P. vivax merozoite. In vitro invasion assays, using blood isolates from individuals in the Mae Sot district of Thailand, showed that addition of rabbit anti-PvDBPII Ab or serum (antibodies against, or serum containing antibodies against, region two of the Plasmodium vivax Duffy binding protein) (1:100) reduced the number of parasite invasions by up to 64%, while pooled PvDBPII antisera from P. vivax-exposed people reduced P. vivax invasion by up to 54%.These results show, for what we believe to be the first time, that both rabbit and human antibodies directed against PvDBPII reduce invasion efficiency of wild P. vivax isolated from infected patients, and suggest that a PvDBP-based vaccine may reduce human blood-stage P. vivax infection.

PMID: 18092885
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