A highly infective Plasmodium vivax strain adapted to Aotus monkeys: Quantitative haematological and molecular determinations useful for P. vivax malaria vaccine development

Coaña, Yago Pico de; Rodríguez, Josefa Antonia; Guerrero, Eduar; Barrero, Carlos; Rodríguez, Ricaurte; Mendoza, Marcela; Patarroyo, Manuel A.

doi:10.1016/s0264-410x(03)00278-0

Cited by 41 publications

(18 citation statements)

References 23 publications

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“…1). The gDNA (extracted using a Wizard Genomic purification kit; Promega, Madison, USA) and cDNA (synthesised with SuperScript III enzyme (RT+) (Invitrogen, Carlsbad, USA) samples from P. vivax VCG-I strain schizont-stage enriched parasites (propagated and obtained as previously described [37, 38]) were used as template in 25 μl PCR reactions containing 1× KAPA HiFi HotStart ReadyMix (KAPA Biosystems, Woburn, MA, USA), 0.3 μM primers and DNAse-free water. Temperature cycling for PCR involved a denaturing step of 95 °C for 5 min, followed by 35 cycles of 98 °C for 20 s, Tm °C (Table 1) for 15 s and 72 °C for 30 s or 1 min and 30 s depending on product size.…”

Section: Methodsmentioning

confidence: 99%

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

et al. 2017

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BackgroundAdhesin proteins are used by Plasmodium parasites to bind and invade target cells. Hence, characterising molecules that participate in reticulocyte interaction is key to understanding the molecular basis of Plasmodium vivax invasion. This study focused on predicting functionally restricted regions of the P. vivax GPI-anchored micronemal antigen (PvGAMA) and characterising their reticulocyte binding activity.ResultsThe pvgama gene was initially found in P. vivax VCG-I strain schizonts. According to the genetic diversity analysis, PvGAMA displayed a size polymorphism very common for antigenic P. vivax proteins. Two regions along the antigen sequence were highly conserved among species, having a negative natural selection signal. Interestingly, these regions revealed a functional role regarding preferential target cell adhesion.ConclusionsTo our knowledge, this study describes PvGAMA reticulocyte binding properties for the first time. Conserved functional regions were predicted according to natural selection analysis and their binding ability was confirmed. These findings support the notion that PvGAMA may have an important role in P. vivax merozoite adhesion to its target cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-017-2183-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

et al. 2017

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“…Since all studies orientated towards developing a rational approach for synthetic vaccines have been carried out in Aotus monkey populations which are highly susceptible to developing human P. falciparum [6] and P. vivax malaria [82], a deep and thorough analysis of their immune system molecules has been undertaken in our institute.…”

Section: Aotus Monkey Immunogeneticsmentioning

confidence: 99%

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Patarroyo

Cifuentes

Salazar

et al. 2005

CMC

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An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite's different developmental stages due to the parasite's remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing. These native and modified HABPs' three-dimensional structure was determined by (1)H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DR beta1* molecules. Our experimental data suggests a correlation between modified HABPs' three-dimensional structure, HLA-DR beta1* binding preferences and their protection-inducing capacity in monkeys. Furthermore, the data presented here indicates that a synthetic peptide vaccine's three-dimensional structural features dictate both HLA-DR beta1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines' protection-inducing value. Basic knowledge of a parasite's functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.

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“…These conserved HABPs were synthesised in polymeric form and used to immunise hundreds of Aotus monkeys (primates which are highly susceptible to developing human malaria) [17,18]. However, conserved HABPs were immunologically silent, since no immune responses were elicited against anyone of them nor protection was induced upon immunisation.…”

Section: Introductionmentioning

confidence: 99%

Shifting the Polarity of some Critical Residues in Malarial Peptides Binding to Host Cells is a Key Factor in Breaking Conserved Antigens Code of Silence

Cifuentes

Bermúdez²,

Rodríguez

et al. 2008

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As microbes use many mechanisms for avoiding immunological pressure, new strategies must be developed to bypass the immunological code of silence of conserved, functionally-important amino acid sequences, such as those involved in high activity binding peptides' (HABPs) attaching to their host cells. Hundreds of experiments in large numbers of Aotus monkeys revealed that this immunological code of silence could be broken by shifting the polarity of some critical host cell binding residues in these HABPs by substituting F for R and vice versa, Y<-->W, L<-->H, I<-->N, P<-->D, M<-->K or E, C<-->T, V<-->N or S; there are special rules for A, G and S. (1)H-nuclear magnetic resonance of these modified, immunogenic, protection-inducing HABPs and molecular modelling revealed that such modifications induced appropriate fitting into specific HLA-DRbeta1 Pockets, suggesting the presence of new pockets and a haplotype- and allele-specific conscious TCR. A highly immunogenic and protection-inducing anti-malarial vaccine can thus be produced.

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A highly infective Plasmodium vivax strain adapted to Aotus monkeys: Quantitative haematological and molecular determinations useful for P. vivax malaria vaccine development

Cited by 41 publications

References 23 publications

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Shifting the Polarity of some Critical Residues in Malarial Peptides Binding to Host Cells is a Key Factor in Breaking Conserved Antigens Code of Silence

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A highly infective Plasmodium vivax strain adapted to Aotus monkeys: Quantitative haematological and molecular determinations useful for P. vivax malaria vaccine development

Cited by 41 publications

References 23 publications

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

PvGAMA reticulocyte binding activity: predicting conserved functional regions by natural selection analysis

Based on HLA-DR&#946;1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Shifting the Polarity of some Critical Residues in Malarial Peptides Binding to Host Cells is a Key Factor in Breaking Conserved Antigens Code of Silence

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Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides