Plasmodium vivax Cell Traversal Protein for Ookinetes and Sporozoites (CelTOS) Functionally Restricted Regions Are Involved in Specific Host-Pathogen Interactions.

Gabriela Arévalo-Pinzón,Maritza Bermúdez,Fredy A Pulido,Manuel A Patarroyo,Diego Garzón-Ospina,Xandy M Rodríguez-Mesa,Johanna Forero-Rodríguez,Leidy P Reyes-Guarín,Carlos F Suárez

doi:10.3389/fcimb.2020.00119

Abstract

Following the injection of Plasmodium sporozoites by a female Anopheles mosquito into the dermis, they become engaged on a long journey to hepatic tissue where they must migrate through different types of cell to become established in parasitophorous vacuoles in hepatocytes. Studies have shown that proteins such as cell traversal protein for Plasmodium ookinetes and sporozoites (CelTOS) play a crucial role in cell-traversal ability. Although CelTOS has been extensively studied in various species and included in pre-clinical assays it remains unknown which P. vivax CelTOS (PvCelTOS) regions are key in its interaction with traversed or target cells (Kupffer or hepatocytes) and what type of pressure, association and polymorphism these important regions could have to improve their candidacy as important vaccine antigens. This work has described producing a recombinant PvCelTOS which was recognized by ~30% P. vivax-infected individuals, thereby confirming its ability for inducing a natural immune response. PvCelTOS' genetic diversity in Colombia and its ability to interact with HeLa (traversal cell) and/or HepG2 cell (target cell) external membrane have been assessed. One region in the PvCelTOS amino-terminal region and another in its C-terminus were seen to be participating in host-pathogen interactions. These regions had important functional constraint signals (ω < 0.3 and several sites under negative selection) and were able to inhibit specific rPvCelTOS binding to HeLa cells. This led to suggesting that sequences between aa 41–60 (40833) and 141–160 (40838) represent promising candidates for an anti-P. vivax subunit-based vaccine.

Highlights

Plasmodium vivax is the second most important species causing human malaria, putting around 35% of the world’s population at risk of infection (Howes et al, 2016)
Even though structural studies have shown that PvCelTOS does not contain disulphide bonds or high complexity structural elements for obtaining it or its stability (Jimah et al, 2016), this study found that natural Ab recognition became significantly reduced when soluble protein produced in E. coli was submitted to high temperatures (Figure 4B)
Similar to that reported regarding other populations, PvCelTOS was seen to be highly conserved and antigenic (Longley et al, 2016; Rodrigues-Da-Silva et al, 2017) only 11 haplotypes were found in more than 200 sequences analyzed from different parts of the world

Summary

Introduction

Plasmodium vivax is the second most important species causing human malaria, putting around 35% of the world’s population at risk of infection (Howes et al, 2016). P. vivax’s biological and epidemiological characteristics impose significant challenges regarding the search for treatment and its biological study (Mueller et al, 2009; Howes et al, 2016) Such characteristics would include its ability to remain in latent hypnozoite form during hepatic stage (leading to repeated relapses and clinical attacks) (White and Imwong, 2012), its high transmission potential caused by high and early gametocyte production, high infectivity in mosquitos and its short development cycle in the vector (Mueller et al, 2009); these have imposed important challenges for designing effective antimalarial treatments and vaccines for this species. Genetic diversity and evolutionary force analysis (drift, selection, and recombination) are useful tools for reducing the amount of candidates to be studied to advance this search

Methods

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Discussion

Conclusion