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

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.

In Silico Analysis Reveals High Levels of Genetic Diversity of Plasmodium knowlesi Cell Traversal Protein for Ookinetes and Sporozoites (PkCelTOS) in Clinical Samples

“…When a mosquito takes a blood meal, the parasite is released in sporozoite form into the host skin. It then initiates gliding motility and cell traversal for penetrating different cell types, e.g., endothelial cells of blood vessels, dermal fibroblasts, phagocytes in sinusoidal and dermal layers (Kupffer cells), and hepatocytes [ 6 , 31 , 51 , 52 ]. This enables the parasites to surpass cellular barriers and access the hepatocytes, where they occupy and mature into liver-stage parasites.…”

“…Cell-traversal protein for ookinetes and sporozoites, briefly known as CelTOS, is a surface protein expressed in sporozoites and ookinetes in the sporogonic stages of Plasmodium’s life cycle. It is an essential micronemal protein that enables the parasite to cross host cell barriers [ 31 , 32 , 33 , 34 ]. It is necessary during parasite invasion into mosquito midgut and human hepatocytes, making it crucial for malaria transmission and disease pathogenesis [ 32 , 33 , 35 ].…”

“…Furthermore, in experimental studies conducted in vivo, it was observed that monoclonal antibodies specifically designed to target PfCelTOS showed significant inhibition of oocyst growth [ 40 ]. This effect was observed in both P. berghei and P. falciparum parasites that expressed PfCelTOS in Anopheles gambiae mosquitoes [ 40 ], suggesting CelTOS as a potential multi-stage vaccine candidate, as blocking this single protein can stop more than one process in the pre-erythrocytic stage [ 31 ]. A recombinant E. coli -expressed PfCelTOS-based vaccine is already in the Phase 1 trial [ 41 ].…”

Plasmodium vivax vaccine: What is the best way to go?

“…PvCelTOS was found to be highly conserved worldwide ( 104 ). A polypeptide of approximately 19 kDa was produced in E. coli , and 30% of patients infected with P. vivax had specific antibodies to recombinant PvCelTOS ( 105 ). To recognize potential B and T-cell epitopes, peptides were analysed, demonstrating that all peptides have regions with potential B-cell epitopes ( 105 ).…”

Naturally acquired antibodies against Plasmodium vivax pre-erythrocytic stage vaccine antigens inhibit sporozoite invasion of human hepatocytes in vitro

“…It plays a critical role in sporozoite egress from host cells during traversal 33 – 36 , which is a necessary part of ookinete infection of the mosquito midgut and sporozoite infection of the liver. P. vivax CelTOS is naturally immunogenic 37 , 38 and immunization of mice with recombinant CelTOS elicits both humoral and cellular immune responses that reduced hepatocyte infection 34 , 37 , 39 – 52 . Antibodies targeting CelTOS can inhibit gliding motility, cell traversal, sporozoite hepatocyte infection, and impaired parasite development in the mosquito 39 , 52 .…”