Abstract
Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner.
Highlights
Theileria annulata and the closely related species, T. parva are ticktransmitted protozoan parasites of cattle
Given the T. annulata infected line, TBL20, has arisen from the infection of a cell line that already displays an immortalised phenotype, reversal of proliferation status and induction of apoptosis may not occur on treatment with BW720c
The results clearly demonstrated that TBL20 cells proliferate at a faster rate than their uninfected counterpart, BL20 (Figure 1)
Summary
Theileria annulata and the closely related species, T. parva are ticktransmitted protozoan parasites of cattle. Establishment of the infected cell phenotype is known to involve constitutive activation of the pro-inflammatory transcription factor NFkB (reviewed in [1]) This is a critical event, as it provides the proliferating infected cell with anti-apoptotic properties [5]. In addition to hijacking host IKK signalosome function, there is evidence that the parasite-infected cell modulates other signalling pathways These include constitutive activation of the AP1 transcription factor [7] by cJUN NH2terminal kinase signalling [8]; induction of TGF-b signalling which appears to be involved in regulation of metastatic potential and virulence of T. annulata infected leukocytes [9] and constitutive phosphoinositide 39-kinase (PI3-K) activity that supports proliferation and possibly contributes to elevation of AP1 and NFkB activity [10]. Such perturbation of multiple signalling events associated with the inflammatory response must have a profound influence on host cell phenotype and the associated profile of gene expression
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