Abstract
The unique biological features of Plasmodium vivax not only make it difficult to control but also to eliminate. For the transmission of the malaria parasite from infected human to the vector, gametocytes play a major role. The transmission potential of a malarial infection is inferred based on microscopic detection of gametocytes and molecular screening of genes in the female gametocytes. Microscopy-based detection methods could grossly underestimate the reservoirs of infection as gametocytes may occur as submicroscopic or as micro- or macro-gametocytes. The identification of genes that are highly expressed and polymorphic in male and female gametocytes is critical for monitoring changes not only in their relative proportions but also the composition of gametocyte clones contributing to transmission over time. Recent transcriptomic study revealed two distinct clusters of highly correlated genes expressed in the P. vivax gametocytes, indicating that the male and female terminal gametocytogeneses are independently regulated. However, the detective power of these genes is unclear. In this study, we compared genetic variations of 15 and 11 genes expressed, respectively, in the female and male gametocytes among P. vivax isolates from Southeast Asia, Africa, and South America. Further, we constructed phylogenetic trees to determine the resolution power and clustering patterns of gametocyte clones. As expected, Pvs25 (PVP01_0616100) and Pvs16 (PVP01_0305600) expressed in the female gametocytes were highly conserved in all geographical isolates. In contrast, genes including 6-cysteine protein Pvs230 (PVP01_0415800) and upregulated in late gametocytes ULG8 (PVP01_1452800) expressed in the female gametocytes, as well as two CPW-WPC family proteins (PVP01_1215900 and PVP01_1320100) expressed in the male gametocytes indicated considerably high nucleotide and haplotype diversity among isolates. Parasite samples expressed in male and female gametocyte genes were observed in separate phylogenetic clusters and likely represented distinct gametocyte clones. Compared to Pvs25, Pvs230 (PVP01_0415800) and a CPW-WPC family protein (PVP01_0904300) showed higher expression in a subset of Ethiopian P. vivax samples. Thus, Pvs230, ULG8, and CPW-WPC family proteins including PVP01_0904300, PVP01_1215900, and PVP01_1320100 could potentially be used as novel biomarkers for detecting both sexes of P. vivax gametocytes in low-density infections and estimating transmission reservoirs.
Highlights
Plasmodium vivax malaria is a neglected tropical disease, despite being more geographically widespread than other forms of malaria (Organization, 2018) and causes 132–391 million clinical infections each year worldwide (Price et al, 2007)
Of the 17 female gametocyte genes, Pvs230 (PVP01_0415800; haplotype diversity (Hd): 0.999 and Pi: 1.24×10-3), GDV1 (PVP01_0734100; Hd: 0.965 and Pi: 2.86×10-3), and ULG8 (PVP01_1452800; Hd: 0.939 and Pi: 1.01×10-3) were the most polymorphic compared to Pvs25 (Figure 1)
Our findings showed that two female gametocyte genes Pvs230 (PVP01_0415800) and ULG8 (PVP01_1425800) were highly polymorphic compared to Pvs25, which are potential DNA markers for determining the source of P. vivax gametocytes and differentiating gametocyte clones within and between hosts
Summary
Plasmodium vivax malaria is a neglected tropical disease, despite being more geographically widespread than other forms of malaria (Organization, 2018) and causes 132–391 million clinical infections each year worldwide (Price et al, 2007). The epidemiology of P. vivax malaria is further complicated by the parasite’s unique ability to form dormant-stage hypnozoites in the host liver cells, resulting in recurrent relapse infections from weeks or months to years later (White, 2011; Chu and White, 2016). Hypnozoites, which remain arrested in the liver for weeks to years, can be activated to cause new blood-stage infections and these features have substantially impacted progress in malaria control, especially in countries that are approaching elimination by providing parasite reservoirs for transmission at any time (Robinson et al, 2015; Lawpoolsri et al, 2019; Taylor et al, 2019)
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