Title: Regulation of the immune response in infectious disease
Funder: The Francis Crick Institute

Abstract: We are researching the molecular mechanisms underlying the development and function of discrete subsets of immune cells that produce different cytokines protective against pathogens, and the induction and function of a regulatory cytokine, IL-10, that on the one hand blocks host pathology but on the other hand can contribute to chronic infection. We use diverse tools to study the mechanisms of IL-10 gene regulation in macrophages, dendritic cells and T cells, and the consequences of IL-10 action in mouse models of diseases. We continue our studies to determine the transcriptional regulation of IL-10 in concert with pro-inflammatory cytokines in lymphoid organs and tissues, in diverse experimental models of Th1, Th2, Th17 and Type I interferon dominated diseases, and plan to further develop these studies to human disease. We have extended our studies of the immune response in infectious diseases, to tuberculosis, in experimental models and human disease. We developed a blood transcriptomic approach to understand the difference between latent/asymptomatic and active tuberculosis in humans. We showed that a blood transcriptional signature, dominated by type I IFN-signalling, was present in the blood of active tuberculosis patients and missing in that of the majority of latent individuals and healthy controls. These findings revealed a hitherto underappreciated role of type I Interferon-αβ signalling in the pathogenesis of tuberculosis. In a subsequent clinical study we showed that the blood signature of tuberculosis distinguishes tuberculosis patients from those with the confounding diseases. We have identified mechanisms whereby type I IFNs can suppress the immune response to M. tuberculosis in part via induction of the immunosuppressive cytokine IL-10 and by direct down-regulation of protective pro-inflammatory cytokines, in experimental models of tuberculosis. We are also developing transcriptomic tools to further analyse the immune response in mouse models of tuberculosis and other diseases to compare and develop these to better resemble human disease and thus provide better platforms for mechanistic studies to help develop better therapeutics. We have since shown that the blood transcriptional signature of tuberculosis is significantly diminished by two weeks after treatment providing a means to monitoring of drug treatment of tuberculosis. We have completed a meta-analysis using 13 publicly available datasets to confirm the reproducibility of the blood based transcriptional analysis and are now developing tools for improved diagnosis and monitoring of tuberculosis -treatment from the blood transcriptomic, for use in the clinic to combat the tuberculosis epidemic. We are developing and refining this signature to determine early tuberculosis disease in humans, and have demonstrated heterogeneity early in the immune response in contacts of TB patients by transcriptomic analyses. This signature was present in individuals who progress to TB disease and absent or transient in those who did not. We will investigate the early immune response in latent and active TB further to understand how individuals are protected or why they go on to develop disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM