Background: Theileria is a unique and remarkable apicomplexan parasite
capable of transforming its host leukocyte into a disseminating cancer-like
tumour and it is the only known example of
natural reversible transformation of mammalian host leukocytes by an eukaryotic
parasite. T. annulata is the
causative agent of the cattle disease called tropical theileriosis, which is of
major economic importance in countries in Northern Africa, The Middle East and
Asia. Importantly, the tumor-like phenotype is reversed upon drug-induced
parasite death. Moreover, virulent macrophages can be attenuated by multiple in
vitro passages, and upon attenuation, they lose both adhesion and
invasiveness. T. annulata-mediated
transformation of host B cells and macrophages is associated with a major
modulation of host cell gene expression involving major transcription factors
genes such as NF-κB, c-Myc and AP and other genes involved in host signaling
pathways and many protein-encoding genes such as MMP9, RASGRP1, GZMA and
non-coding RNAs such as miR126, miR155 have been functionally implicated
in Theileria-mediated leukocyte
transformation and dissemination. With the availability of next generation
sequencing technologies (such as Illumina miRNA-seq), it is possible to obtain
an unbiased and comprehensive catalogue of miR gene expression and an understanding
of their perturbations due to T.
annaulata-mediated leukocyte transformation. In a recent study, miRNA-seq
was used to define the miR-expression landscapes of T. annulata-transformed B-cell and macrophage cell lines and we
have identified several oncogenic miRs relevant to cellular transformation and
dissemination. Bioinformatic comparisons of the miR expression catalogues has identified
several candidate novel miR-like sequences whose expresson is modulated during
infection.
Objectives: In this study, we aim to
functionally verify the existence of potential novel miRs relevant to infection
and functionally characterize their roles in Theileria-mediated transformation of bovine host host cells and eventually
explore if these miRs are indeed also present and expressed in human and play
any role in cell proliferation and dissemination during tumorigenesis.
Methodology: We propose to bioinformatically re-analyse the miRnome
datasets generated previously by our group to look for novel miRs and quantify
their expression landscapes by Q-RT-PCR and finally test their functional roles
and cellular targets by routine cell biology techniques with inhibitors and
over expression of novel miR candidates. Finally, we will be screening a panel
of human cancel lines to check for their existence in the context of human
cancer progession and dissemination phenotype.
This study will be performed in active
collaboration with KAUST experts in the tumorigenesis field.