Theileria’s Strategies and Effector Mechanisms for Host Cell Transformation: From Invasion to Immortalization

Abstract

One of the first events that follows invasion of leukocytes by Theileria sporozoites is the destruction of the surrounding host cell membrane and the rapid association of the intracellular parasite with host microtubules. This is essential for the parasite to establish its niche within the cytoplasm of the invaded leukocyte and sets Theileria spp. apart from other members of the apicomplexan phylum such as Toxoplasma gondii and Plasmodium spp., which reside within the confines of a host-derived parasitophorous vacuole. After establishing infection, transforming Theileria species (T. annulata, T. parva) significantly rewire the signaling pathways of their bovine host cell, causing continual proliferation and resistance to ligand-induced apoptosis, and conferring invasive properties on the parasitized cell. Having transformed its target cell, Theileria hijacks the mitotic machinery to ensure its persistence in the cytoplasm of the dividing cell. Some of the parasite and bovine proteins involved in parasite-microtubule interactions have been fairly well characterized, and the schizont expresses at least two proteins on its membrane that contain conserved microtubule binding motifs. Theileria-encoded proteins have been shown to be translocated to the host cell cytoplasm and nucleus where they have the potential to directly modify signaling pathways and host gene expression. However, little is known about their mode of action, and even less about how these proteins are secreted by the parasite and trafficked to their target location. In this review we explore the strategies employed by Theileria to transform leukocytes, from sporozoite invasion until immortalization of the host cell has been established. We discuss the recent description of nuclear pore-like complexes that accumulate on membranes close to the schizont surface. Finally, we consider putative mechanisms of protein and nutrient exchange that might occur between the parasite and the host. We focus in particular on differences and similarities with recent discoveries in T. gondii and Plasmodium species.

Characterisation of the Theileria orientalis Piroplasm Proteome across Three Common Genotypes

“…Theileria spp. contain microspheres, equivalent to the dense granules of T. gondii, during the sporozoite phase but not the schizont phase [ 39 ]. It is unclear whether these are present during the piroplasm phase [ 40 ].…”

Plasmepsin-like Aspartyl Proteases in Babesia

“…This role supposedly might be played by the newly identified Babesia ASP3b isoenzyme. Similarly, Theileria's surface coat is shed by an undescribed protease, suggesting an identical role of the Theileria ASP3b orthologues [62]. Initial attachment of the parasite to the host erythrocyte is followed by the reorientation of the apical tip towards the host cell, and the establishment of the moving (tight) junction (MJ) [63].…”

“…Both Plasmodium and Toxoplasma use sophisticated protein transporting complexes PTEX (plasmodium translocon of exported proteins) and the MYR translocon, respectively, which are incorporated into the PVM [92,93]. Unsurprisingly, piroplasms do not encode for components of the Plasmodium translocon machinery [29], with the single exception of the PTEX complex protein component HSP101, which is expressed across all piroplasms [62].…”

“…While SmORFs are also involved in erythrocyte adhesion [95,96], SBP2 proteins concentrate under the red blood cell cytoplasmic membrane and are believed to alternate the red blood cell surface [99]. Although PLM has not yet been detected in Theileria [62,97], the apparent conservation of clade D APs within the phylum suggests the preserved mode of protein processing across Piroplasmida. Further studies on clade D APs should further elucidate the exact role of these enzymes in the trafficking mechanisms of Babesia spp.…”

Detection of Theileria orientalis Genotypes from Cattle in Kyrgyzstan

“…It is known that Theileria parva and Theileria annulata , which are also known as transforming species, are highly pathogenic species for cattle. Other species of Theileria that infect cattle, Theileria mutans , Theileria taurotragi , and members of the Theileria orientalis complex, frequently cause benign infections [ 3 , 4 , 5 ]. It has been observed that Theileria orientalis , long thought to be benign, has different genotypes, some of which cause clinical cases and adversely affect the cattle industry [ 6 ].…”