Expression, Purification, and Characterization of the Immunological Response to a 40-Kilodalton<i>Plasmodium vivax</i>Tryptophan-Rich Antigen

Plasmodium vivax is a very common but non-cultivable malaria parasite affecting large human population in tropical world. To develop therapeutic reagents for this malaria, the parasite molecules involved in host-parasite interaction need to be investigated as they form effective vaccine or drug targets. We have investigated here the erythrocyte binding activity of a group of 15 different Plasmodium vivax tryptophan rich antigens (PvTRAgs). Only six of them, named PvTRAg, PvTRAg38, PvTRAg33.5, PvTRAg35.2 PvTRAg69.4 and PvATRAg74, showed binding to host erythrocytes. That the PvTRAgs binding to host erythrocytes was specific was evident from the competitive inhibition and saturation kinetics results. The erythrocyte receptors for these six PvTRAgs were resistant to trypsin and neuraminidase. These receptors were also chymotrypsin resistant except the receptors for PvTRAg38 and PvATRAg74 which were partially sensitive to this enzyme. The cross-competition studies showed that the chymotrypsin resistant RBC receptor for each of these two proteins was different. Altogether, there seems to be three RBC receptors for these six PvTRAgs and each PvTRAg has two RBC receptors. Both RBC receptors for PvTRAg, PvTRAg69.4, PvTRAg33.5, and PvTRAg35.2 were common to all these four proteins. These four PvTRAgs also shared one of their RBC receptors with PvTRAg38 as well as with PvATRAg74. The erythrocyte binding activity of these six PvTRAgs was inhibited by the respective rabbit polyclonal antibodies as well as by the natural antibodies produced by the P. vivax exposed individuals. It is concluded that only selective few PvTRAgs show erythrocyte binding activity involving different receptor molecules which can be blocked by the natural antibodies. Further studies on these receptor and ligands may lead to the development of therapeutic reagents for P. vivax malaria.

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“…These Plasmodium vivax tryptophan-rich proteins are expressed during blood stages of the parasite [24]–[27], [29]. Some of them, e.g.…”

Section: Discussionmentioning

confidence: 99%

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Tyagi

Sharma

2012

PLoS ONE

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“…Tryptophan‐rich proteins of P. vivax belong to ‘Pv‐fam‐a’ family and there is a stage‐specific expression of these proteins in the parasite, probably to perform different functions . Previously, we immunobiologically characterized large numbers of these proteins and hypothesized that some of them may be involved in red cell invasion . These proteins have exceptionally high tryptophan contents and the tryptophan residues are positionally conserved with a certain spatial pattern.…”

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Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

et al. 2016

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Tryptophan-rich antigens of malarial parasites interact with host molecules and play an important role in parasite survival. Merozoite expressed Plasmodium vivax tryptophan-rich antigen PvTRAg38 binds to human erythrocytes and facilitates parasite growth in a heterlologous Plasmodium falciparum culture system. Recently, we identified band 3 in human erythrocytes as one of its receptors, although the receptor-ligand binding mechanisms remain unknown. In the present study, using synthetic mutated peptides of PvTRAg38, we show that multiple amino acid residues of its 12 amino acid domain (KWVQWKNDKIRS) at position 197-208 interact with three different ectodomains of band 3 receptor on human erythrocytes. Our findings may help in the design of new therapeutic approaches for malaria.

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“…Although antibody levels in patient sera and cytokine levels against some P. vivax antigens have been studied (16,25,26), there is a lack of information about the induction of CD4 ϩ T cells and their cross talk with B cells in malaria patients which could generate stronger immune response to minimize P. vivax infection. Here, we analyzed antibody responses and the effector immune responses of CD4 ϩ T cells among P. vivax-exposed individuals against the remaining 21 PvTRAgs, in addition to the genetic polymorphism.…”

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“…As a result, there are fewer P. vivax than P. falciparum vaccine candidate antigens being tested in clinical trials. In fact, very few P. vivax antigens have been immunologically characterized to determine their potential as vaccine candidates.Tryptophan-rich proteins have been identified in murine and human malaria parasites (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Across the Plasmodium species, these proteins have positionally conserved tryptophan residues.…”

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CD4 ⁺ T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens

2015

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Tryptophan-rich proteins play important biological functions for the Plasmodium parasite. Plasmodium vivax contains remarkably large numbers of such proteins belonging to the "Pv-fam-a" family that need to be characterized. Earlier, we reported the presence of memory T cells and naturally acquired antibodies against 15 of these proteins in P. vivax malaria-exposed individuals (M. Zeeshan, H. Bora, and Y. D. Sharma, J Infect Dis 207:175-185, 2013, http://dx.doi.org/10.1093/infdis/jis650). Here, we sought to characterize and ascertain the cross talk between effector responses of T and B cells in malarial patients against all Pvfam-a family proteins. Therefore, we expressed the remaining 21 of these proteins in Escherichia coli and studied the humoral and cellular immune responses based on the same parameters used in our previous study. Naturally acquired IgG antibodies were detected against all 21 antigens in P. vivax patient sera (37.7 to 94.4% seropositivity). These antigens were able to activate the lymphocytes of P. vivax-exposed individuals, and the activated CD4 ؉ T lymphocytes produced higher levels of Th1 (interleukin-2 [IL-2] and gamma interferon [IFN-␥]) and Th2 (IL-4 and IL-10) cytokines than the healthy controls, but the response was Th2 biased. The combined results of present and previous studies seem to suggest a striking link between induction of the CD4 ؉ T cell response and naturally acquired antibodies against all 36 proteins of the Pv-fam-a family, the majority of them having conserved sequences in the parasite population. Further work is required to utilize this information to develop immunotherapeutic treatments for this disease. Despite continued efforts to control malaria, it remains a major health problem in affected tropical countries. There is an urgent need to develop an effective malaria vaccine and newer antimalarial drugs to control this disease. This requires the identification and characterization of newer parasite molecules that play significant biological function for the survival of the parasite and could generate cellular and humoral immune responses in humans to provide protection against the disease. Previous studies have shown that humoral and T-cell-mediated immune responses are induced against malaria parasite, and these responses were found to be antigen and stage specific (1). Antibodies come to play their role as soon as the parasite enters the human body. These antibodies not only clear the parasite by opsonization but also block the invasion of host cells by the parasite. Therefore, the humoral immune response plays a critical role in controlling the parasite.A role for dendritic cells, monocyte/macrophages, B cells, and several groups of T cells has been proposed in the cellular immune response against malaria (1-4). Some specific cytokines are produced from peripheral blood mononuclear cells in response to parasite infection, which further activates the host's macrophages, neutrophils, T cells, and natural killer cells to react against the parasites (5). Monocytes/ma...

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Expression, Purification, and Characterization of the Immunological Response to a 40-KilodaltonPlasmodium vivaxTryptophan-Rich Antigen

Cited by 15 publications

References 34 publications

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

CD4 ⁺ T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens

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Expression, Purification, and Characterization of the Immunological Response to a 40-KilodaltonPlasmodium vivaxTryptophan-Rich Antigen

Cited by 15 publications

References 34 publications

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

CD4 + T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens

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CD4 ⁺ T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens