Modulation of activation‐associated host cell gene expression by the apicomplexan parasiteTheileria annulata

Abstract

SummaryInfection of bovine leucocytes by Theileria annulata results in establishment of transformed, infected cells. Infection of the host cell is known to promote constitutive activation of pro-inflammatory transcription factors that have the potential to be beneficial or detrimental. In this study we have compared the effect of LPS activation on uninfected bovine leucocytes (BL20 cells) and their Theileria-infected counterpart (TBL20). Gene expression profiles representing activated uninfected BL20 relative to TBL20 cells were also compared. The results show that while prolonged stimulation with LPS induces cell death and activation of NF-κB in BL20 cells, the viability of Theileria-infected cells was unaffected. Analysis of gene expression networks provided evidence that the parasite establishes tight control over pathways associated with cellular activation by modulating reception of extrinsic stimuli and by significantly altering the expression outcome of genes targeted by infection-activated transcription factors. Pathway analysis of the data set identified novel candidate genes involved in manipulation of cellular functions associated with the infected transformed cell. The data indicate that the T. annulata parasite can irreversibly reconfigure host cell gene expression networks associated with development of inflammatory disease and cancer to generate an outcome thatis beneficial to survival and propagation of the infected leucocyte.

Regulation of Trypanosoma brucei Total and Polysomal mRNA during Development within Its Mammalian Host

“…Hence, these are potentially subject to non-systematic variations resulting from growth in vivo, the given strain analysed and parasite isolation procedures. This variation is apparent when comparing the genes enriched in stumpy cells in different analyses with those enriched in stumpy cells in our study, although we found the best agreement (p<0.001, using a Monte Carlo simulation using 1000 iterations [50]) with the study by Jensen and colleagues [17] ( Data File S9 ). The importance of different isolation procedures for different studies is revealed in the SILAC analysis of stumpy forms where PAD2 was seen to be strongly expressed, likely reflective of parasite cold shock or the induction of early differentiation events during isolation procedures [44].…”

Proteomic analysis of the Theileria annulata schizont

“…This is facilitated by the fact that, immediately following entry into the leukocyte, the host cell membrane surrounding the invading sporozoite is dissolved, leaving the developing schizont free in the cytoplasm where it can interact with the host cell cytoskeleton and regulatory components of signalling pathways. Analysis of leukocyte gene expression networks provided evidence that the parasite establishes tight control over pathways associated with cellular activation by modulating reception of extrinsic stimuli and by significantly altering the expression outcome of genes targeted by infection-activated transcription factors (Durrani et al, 2012). Furthermore, at each host cell mitosis and cytokinesis, the schizont co-opts the host’s astral and central spindle microtubules, ensuring its equal distribution between the two daughter cells (Hulliger et al, 1964; von Schubert et al, 2010).…”

Theileria-transformed bovine leukocytes have cancer hallmarks

“…Therefore, it is not surprising that some Theileria species have evolved mechanisms to directly modify host signaling pathways similarly to some cancers [34,35]. We propose that each of the hallmarks that Theileria transformation shares with some cancer cells represents an opportunity for insights into host pathogenesis (Box 1) and potentially new therapeutic approaches for parasite infection.…”

“…In contrast to both normal somatic cells and many cancer cells, T. parva-transformed lymphocytes require contact with other infected or uninfected cells to proliferate [85]. The expression levels of known regulators of contact inhibition, Merlin or liver kinase B1, are not reportedly regulated by T. annulata during infection [34,35], suggesting that Theileria-infected cells may achieve contact independence via an as-yet undiscovered mechanism.…”

“…A bTERTtargeted vaccine against Theileria infection is also an intriguing possibility because hTERT has been the target of vaccine trials for human cancers [33]. However, bTERT was not reported to be differentially expressed during infection of bovine B-lymphosarcoma cells by T. annulata [34,35], indicating that Theileria transformation may use an alternative mechanism to lengthen telomeres, or that existing telomerase may be hyperactivated.…”