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.
Genetic analyses of patients with Primary Immunodeficiencies
Primary Immunodeficiencies (PIDs) comprise a heterogeneous group of genetic disorders that affect functioning of the immune system and manifest as severe and/or recurrent infections. Mutations in more than 200 genes are known to cause various PIDs. We study PID patients in collaboration with clinical scientists at the Addenbrooke’s Hospital and across the UK and Europe. We use whole exome sequencing to search for causative mutations, followed by detailed functional molecular analyses of the affected cellular pathways.
Recently, we discovered a novel PID called Activated PI3K-Delta Syndrome (APDS), which is caused by a dominant gain-of-function mutation in the Phosphoinositide 3-kinase δ Gene (Angulo et al, Science, 2013). APDS patients have antibody deficiency, suffer recurrent respiratory infections and rapidly develop airway damage (bronchiectasis). Our study suggests that selective PI3Kδ inhibitors may provide a novel specific and efficient treatment approach for APDS patients.
Angulo et al paper is available here.
For more information about APDS click here.
Genetics of susceptibility to tuberculosis
We have particular interest in understanding susceptibility to tuberculosis (TB) and mycobacterial infection. We have established the world’s largest collection of DNA samples from >6,000 HIV-negative patients diagnosed with pulmonary TB and >8,000 geographically and ethnically matched healthy controls.
In collaboration with the Wellcome Trust Sanger Institute we now undertake a genome-wide association study (GWAS) in 11,000 TB patients and controls using Affymetrix Genome-Wide Human SNP Array 6.0 genotyping array that includes probes for >900,000 single nucleotide polymorphisms (SNPs) and >940,000 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.
Our lab is a member of the TB-EUROGEN consortium, where we collaborate with groups that study 2,600 clinical M. tuberculosisisolates 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 a 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.