Abstract
Plasmodium vivax (Pv) malaria continues to be geographically widespread with approximately 15 million worldwide cases annually. Along with other proteins, Duffy-binding proteins (DBPs) are used by plasmodium for RBC invasion and the parasite-encoded receptor binding regions lie in their Duffy-binding-like (DBL) domains—thus making it a prime vaccine candidate. This study explores the sequence diversity in PvDBL globally, with an emphasis on India as it remains a major contributor to the global Pv malaria burden. Based on 1358 PvDBL protein sequences available in NCBI, we identified 140 polymorphic sites within 315 residues of PvDBL. Alarmingly, country-wise mapping of SAAPs from field isolates revealed varied and distinct polymorphic profiles for different nations. We report here 31 polymorphic residue positions in the global SAAP profile, most of which map to the PvDBL subdomain 2 (α1–α6). A distinct clustering of SAAPs distal to the DARC-binding sites is indicative of immune evasive strategies by the parasite. Analyses of PvDBL-neutralizing antibody complexes revealed that between 24% and 54% of interface residues are polymorphic. This work provides a framework to recce and expand the polymorphic space coverage in PvDBLs as this has direct implications for vaccine development studies. It also emphasizes the significance of surveying global SAAP distributions before or alongside the identification of vaccine candidates.
Highlights
Malaria remains a serious public health concern for large swathes of the world
For each collected blood sample (n = 176), genomic DNA was isolated using the QIAamp DNA mini kit (Qiagen, Germany) according to the manufacturer’s instructions. Because both Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) occur in India in almost equal proportions [58], we confirmed the presence of Pf and Pv using nested polymerase chain reaction (PCR) assays with genusand species-specific oligonucleotide primers based on the 18S rRNA gene [59]
Protein sequence analysis of PvDBL among 171 Pv isolates from India revealed that there were 37 polymorphic residue positions which contained 40 single amino acid polymorphisms (SAAPs), of which 24 SAAPs occurred with a frequency of 1% and above
Summary
Malaria remains a serious public health concern for large swathes of the world. Of the five plasmodia species that cause human malaria, Plasmodium falciparum (Pf ) is responsible for most mortality, but in Asia and South America, Plasmodium vivax (Pv) is a significant cause of morbidity [1]. Most of the parasite proteins involved in such interactions are potential targets for the human immune system and display extensive polymorphisms as a mechanism for immune evasion [11,12]. One such candidate for Pv is the cysteine-rich Duffy-binding protein (DBP), which is in a subset of the erythrocyte-binding antigens (EBAs) [13,14]. Other non-polar and hydrophobic residues that are important for DBL–DARC interaction to be maintained include K289, Y295, N296, F299, Y363, K366, K367, L369, F373 and I376 [11,27,31,32] These are collectively referred to as DARC-. We here provide both new PvDBL sequences from across India and use the PvDBL sequences recorded in GenBank to assess the extent of non-synonymous single-nucleotide polymorphisms which give rise to single amino acid polymorphisms (SAAPs)
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