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Our work
We are searching for genes in the human genome that carry sequence variants, which are involved in resistance to infection and predispose to infectious diseases. Discovery of such genes can open new biological pathways and suggest new targets for intervention. We use methods of human genetics, including genome-wide association studies (GWAS) and exome sequencing, in vitro models of infection and methods of molecular biology to understand underlying biological mechanisms protecting from infection.
Genetics of susceptibility to tuberculosis
Our research focuses on susceptibility to tuberculosis (TB) and mycobacterial infection. Our group is part of a consortium called TB-EUROGEN that brings together TB clinicians, experts in human genetics and mycobacterial research. We have established the world’s largest collection of DNA samples from 6,000 HIV-negative patients diagnosed with pulmonary TB and 6,000 geographically and ethnically matched healthy controls.
In collaboration with the Wellcome Trust Sanger Institute we now undertake a genome-wide association study (GWAS) in 12,000 TB patients and controls using Affymetrix SNP 6.0 genotyping array that include probes for 906,600 single nucleotide polymorphisms (SNPs) and more than 946,000 probes for the detection of copy number variation (CNVs) spread across the genome. We statistically compare frequencies of these variants in the groups of TB patients and healthy controls aiming to discover genomic regions that are associated with TB. These experiments will reveal human genes that predispose to or protect from TB and may highlight new pathways that are involved in control of M. tuberculosis infection and progression to pulmonary TB.
In the TB-EUROGEN consortium we collaborate with groups that study 2,600 clinical M. tuberculosis isolates collected from the same TB patients. We combine information obtained in these experiments to investigate interaction between human genes that predispose to TB and virulence factors of mycobacteria. Eventually, our study will lead to better understanding of TB pathogenesis and may suggest new strategies for TB prevention.
Understanding biological mechanisms involved in mycobacterial infection using in vitro cell models.
In this project we study healthy volunteers participating in Cambridge BioResource. We isolate immune cells from blood samples of the volunteers and use in vitro models of mycobacterial infection and transcriptome analyses to investigate mechanisms that human cells utilise to contain and eliminate mycobacteria. We compare genetic information from different people and their immune cell responses upon infection in vitro. Our goal is to discover sequence variants, genes and biological pathways that are involved in protection from mycobacteria.
Genetic analyses of patients with Mendelian susceptibility to mycobacterial infections.
While susceptibility to common pulmonary TB is a complex multifactorial phenotype, susceptibility to severe disseminated mycobacterial infections is known to be caused by single gene mutations. Such Mendelian mutations have strong biological impacts that profoundly affect human immune system. In collaboration with Drs Rainer Doffinger and Dinakantha Kumararatne at the Addenbrooke’s Hospital we study patients with severe disseminated mycobacterial disease to discover new relevant genes and study their role in mycobacterial infection. We use whole exome sequencing to search for causative mutations, followed by detailed functional molecular analyses of the affected cellular pathways.
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