Abstract
Thrombospondin-related adhesive protein (TRAP) of malaria parasites is essential for sporozoite motility and invasions into mosquito’s salivary gland and vertebrate’s hepatocyte; thereby, it is a promising target for pre-erythrocytic vaccine. TRAP of Plasmodium vivax (PvTRAP) exhibits sequence heterogeneity among isolates, an issue relevant to vaccine development. To gain insights into variation in the complete PvTRAP sequences of parasites in Thailand, 114 vivax malaria patients were recruited in 2006–2007 from 4 major endemic provinces bordering Myanmar (Tak in the northwest, n = 30 and Prachuap Khirikhan in the southwest, n = 25), Cambodia (Chanthaburi in the east, n = 29) and Malaysia (Yala and Narathiwat in the south, n = 30). In total, 26 amino acid substitutions were detected and 9 of which were novel, resulting in 44 distinct haplotypes. Haplotype and nucleotide diversities were lowest in southern P. vivax population while higher levels of diversities were observed in other populations. Evidences of positive selection on PvTRAP were demonstrated in domains II and IV and purifying selection in domains I, II and VI. Genetic differentiation was significant between each population except that between populations bordering Myanmar where transmigration was common. Regression analysis of pairwise linearized Fst and geographic distance suggests that P. vivax populations in Thailand have been isolated by distance. Sequence diversity of PvTRAP seems to be temporally stable over one decade in Tak province based on comparison of isolates collected in 1996 (n = 36) and 2006–2007. Besides natural selection, evidences of intragenic recombination have been supported in this study that could maintain and further generate diversity in this locus. It remains to be investigated whether amino acid substitutions in PvTRAP could influence host immune responses although several predicted variant T cell epitopes drastically altered the epitope scores. Knowledge on geographic diversity in PvTRAP constitutes an important basis for vaccine design provided that vaccination largely confers variant-specific immunity.
Highlights
In low- and middle-income countries in tropical areas, malaria remains one of the leading ten causes of morbidity and mortality, resulting in an estimated economic loss of nearly 40 million disability-adjusted life-years (DALYs) [1]
Plasmodium falciparum is the most pernicious and prevalent species, the significance of P. vivax should not be underappreciated because it can cause chronic relapsing illness due to reactivation of hypnozoites and it can potentially lead to severe complications similar to those caused by P. falciparum [2]
Closer look into amino acid substitutions and potential HLA-binding peptides as predicted by the high scores for the C-terminal cleavage and the transporter associated with antigen processing efficiency [48] have shown that a number of substituted residues have remarkably reduced predicted scores; thereby, the property of these epitopes could be altered
Summary
In low- and middle-income countries in tropical areas, malaria remains one of the leading ten causes of morbidity and mortality, resulting in an estimated economic loss of nearly 40 million disability-adjusted life-years (DALYs) [1]. Because P. vivax and P. falciparum co-circulate in several endemic areas outside Africa where co-infections of both species are not uncommon [5], effective malaria control requires vaccines against both species. Co-immunization of CSP with thrombospondin-related adhesive protein (TRAP), a protein mobilized from microneme to the surface of sporozoite [9], has conferred complete protection against parasite challenge whereas vaccination using each of these immunogens could elicit only partial protection [10]. It is important to note that TRAP-specific CD8+ T lymphocytes are prime mediators for protection against sporozoite challenge in mouse vaccination trials, resulting in significant reduction in liver stage parasites [11]. Seroepidemiological study has shown that anti-TRAP antibodies were negatively correlated with parasite density among infected individuals in malaria endemic areas [12]
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