Extensive genetic diversity of Plasmodium vivax dbp-II in Rio de Janeiro Atlantic Forest and Brazilian Amazon Basin: evidence of positive selection

Abstract

Background: Plasmodium vivax is the most widespread human malaria parasite outside Africa and is the predominant parasite in the Americas. Increasing reports of P. vivax disease severity, together with the emergence of drugresistant strains, underscore the urgency of the development of vaccines against P. vivax. Polymorphisms on DBP-IIgene could act as an immune evasion mechanism and, consequently, limited the vaccine efficacy. This study aimed to investigate the pvdbp-II genetic diversity in two Brazilian regions with different epidemiological patterns: the unstable transmission area in the Atlantic Forest (AF) of Rio de Janeiro and; the fixed malaria-endemic area in Brazilian Amazon (BA).Methods: 216 Brazilian P. vivax infected blood samples, diagnosed by microscopic examination and PCR, were investigated. The region flanking pvdbp-II was amplified by PCR and sequenced. Genetic polymorphisms of pvdbp-II were estimated based on the number of segregating sites and nucleotide and haplotype diversities; the degree of differentiation between-regions was evaluated applying Wright's statistics. Natural selection was calculated using the rate of nonsynonymous per synonymous substitutions with the Z-test, and the evolutionary distance was estimated based on the reconstructed tree.Results: 79 samples from AF and 137 from BA were successfully sequenced. The analyses showed 28 polymorphic sites distributed in 21 codons, with only 5% of the samples Salvador 1 type. The highest rates of polymorphic sites were found in B-and T cell epitopes. Unexpectedly, the nucleotide diversity in pvdbp-II was higher in AF (0.01) than in BA (0.008). Among the 28 SNPs detected, 18 are shared between P. vivax isolates from AF and BA regions, but 8 SNPs were exclusively detected in AF-I322S, K371N, E385Q, E385T, K386T, K411N, I419L and I419R-and 2 (N375D and I419M) arose exclusively in BA. These findings could suggest the potential of these geographical clusters as population-specific-signatures that may be useful to track the origin of infections. The sample size should be increased in order to confirm this possibility. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Conclusions:The results highlight that the pvdbp-II polymorphisms are positively selected by host's immune pressure. The characterization of pvdbp-II polymorphisms might be useful for designing effective DBP-II-based vaccines.

Balancing selection and high genetic diversity of Plasmodium vivax circumsporozoite central region in parasites from Brazilian Amazon and Rio de Janeiro Atlantic Forest

“…This constrained variation in terminal regions reinforces such protein structures importance for its interaction with Anopheles mosquito salivary gland and human hepatocytes during the invasion processes [52]. Conversely, CR diversity could reflect the host's immune system's evasion mechanism, as already observed for other surface antigens as pvdbp gene [12,68].…”

Geographical distribution and genetic diversity of Plasmodium vivax reticulocyte binding protein 1a correlates with patient antigenicity

“…The most advanced P. vivax vaccine candidate to date is PvDBP-RII (268-513 aa.). The pvdbp gene has been show to exhibit high genetic diversity in Malaysia (π = 0.01000), Brazil (π = 0.01200) [45], and Myanmar (π = 0.00400-0.00600), as well as evidence of positive selection pressure [12,[46][47][48][49]. The PvDBP-RII fragment is a functional domain containing 12 conserved-cysteine residues, with a conserved protein structure and binding functions to DARC [50].…”

Genetic Diversity and Natural Selection of Plasmodium vivax Duffy Binding Protein-II From China-Myanmar Border of Yunnan Province, China

“…The PvDBP-II is highly polymorphic compared to the rest of the region. Genetic analysis from different geographical P. vivax isolates demonstrated that this region is under positive selection, with polymorphic residues varying by geographic region ( Ampudia et al, 1996 ; Xainli et al, 2000 ; Ju et al, 2013 ; Chootong et al, 2014 ; Almeida-de-Oliveira et al, 2020 ). Despite PvDBP-II presenting a promising vaccine antigenic, diversity may affect the immune recognition and host immune response which may reflect that polymorphisms of PvDBP-II help in immune evasion mechanism ( Cole-Tobian and King, 2003 ).…”