Infection of bovine cells by the protozoan parasite Theileria annulata modulates expression of the ISGylation system

Abstract

SummaryThe apicomplexan parasite, Theileria annulata , dedifferentiates and induces continuous division of infected bovine myeloid cells. Re-expression of differentiation markers and a loss of proliferation occur upon treatment with buparvaquone, implying that parasite factors actively maintain the altered status of the infected cell. The factors that induce this unique transformation event have not been identified. However, parasite polypeptides (TashAT family) that are located in the infected leucocyte nucleus have been postulated to function as modulators of host cell phenotype. In this study differential RNA display and proteomic analysis were used to identify altered mRNA and polypeptide expression profiles in a bovine macrophage cell line (BoMac) transfected with TashAT2 . One of the genes identified by differential display was found to encode an ubiquitin-like protease (bUBP43) belonging to the UBP43 family. The bUBP43 gene and the gene encoding its ubiquitin-like substrate, bISG15, were expressed at a low level in T. annulata -infected cells. However, infected cells were refractory to induction of elevated bISG15 expression by lipopolysaccharide or type 1 interferons while TashAT2 -transfected cells showed no induction when treated with camptothecin. Modulation of the ISGylation system may be of relevance to the establishment of the transformed infected host cell, as ISGylation is associated with resistance to intracellular infection by pathogens, stimulation of the immune response and terminal differentiation of leukaemic cells.

Highly syntenic and yet divergent: A tale of two Theilerias

“…Thus, genes flanking the cluster are more likely to perform a function conserved across the species while internal genes may have evolved during species diversification, including adaptation to a preferred host cell type. A predicted function for TashAT family proteins is that they act as DNA binding cofactors, which direct the expression of genes targeted by bovine transcription factors (such as AP1 and NF-kB) constitutively activated following infection of the leukocyte by both species (Oura et al, 2006). Theileria is similar to Plasmodia, but their usage is less polarised, probably reflecting the greater AT-richness of P. falciparum coding sequences compared to Theileria.…”

Theileria-transformed bovine leukocytes have cancer hallmarks

“…TashAT-family proteins are secreted by the parasite, some of which localize to the host nucleus, and one has been found to alter the expression of the IFN-inducible bovine gene ISG15 [97]. These proteins display a high degree of sequence conservation in their DNA-binding domains in T. annulata.…”

Tick-borne diseases in cattle: Applications of proteomics to develop new generation vaccines

“…transform host cell (leucocytes) inducing uncontrolled proliferation [60,61]. However, the parasite factors responsible for the inhibition of host cell apoptosis or induction of host cell proliferation are unknown.…”

“…The authors suggest that to transform host cells, Theileria spp. might modulate the ISGylation system, a key mechanisms associated with resistance of host cells to intracellular infection by pathogens, stimulation of the immune response and terminal differentiation of leukemic cells [61].…”