Roles of novel miRNAs in leukocyte transformation – using Theileria-leukocyte transformation as a model

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Project Description

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.  ​​
Program - BioScience
Division - Biological and Environmental Sciences and Engineering
Field of Study - ​Microbiology, Molecular Biology, Cell biology, Parasitology

About the
Researcher

Arnab Pain

Professor, Bioscience

Arnab Pain
The primary focus of the Pathogen Genomics Laboratory is to use high-throughput sequencing and other functional genomic technologies to understand the biology and genomic diversity of a few parasitic protists and bacteria with significant impact on human and animal health. Genome and transcriptome sequencing of these organisms is a critical first step towards our understanding of how these organisms grow and thrive in a susceptible host and in other environment. A better understanding of their biology could eventually lead to the development of new intervention strategies.

Within this program, a combination of high-throughput DNA and RNA sequencing-based methods, coupled with functional genomics and bioinformatics tools are being used in the following areas of research:
  1. Genomics of Apicomplexan parasites and Chromerids and host-parasite interactions. 
  2. Molecular and genomic characterization of enteric pathogens particularly during mass gatherings 
  3. Genome variation in Mycobacteria 
  4. Development of bioinformatic tools for genome-scale data visualization and mining

Desired Project Deliverables

​This study is expected to discover previously unknown miRs and their cellular targets / functions not only in Theileria-mediated leukocyte transformation and dissemination but also thei potential roles in mammalian cell proliferation and dissemination.