Transcriptomics reveal the immune response in tuberculosis:Type I IFN response in tuberculosis: foe & occasionally friend
Tuberculosis remains a major cause of morbidity and mortality worldwide, but despite its clinical significance, there are still major gaps in our understanding of pathogenic and protective mechanisms triggered by Mycobacterium tuberculosis infection. Type I interferons (IFN) regulate a broad family of genes that either stimulate or inhibit immune function, having both host-protective and detrimental effects, and exhibit well-characterized antiviral activity. Using blood transcriptomic analyses, we revealed that the tuberculosis signature was dominated by an interferon (IFN)-inducible gene profile, consisting of both IFN- and Type I IFNαβ signaling, and suggested a hitherto under-appreciated role of Type I IFNαβ signalling in human tuberculosis pathogenesis. Since then, additional studies in human tuberculosis and experimental mouse models of M. tuberculosis infection support the concept that high levels of type I IFN promote both bacterial expansion and disease pathogenesis. More recently, however, in studies in a different setting we suggest a putative protective role for type I IFN. I will discuss the mechanistic and contextual factors that determine the detrimental versus beneficial outcomes of type I IFN induction during M. tuberculosis infection, from human disease to experimental mouse models of tuberculosis.
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O’Garra pioneered studies demonstrating the role of cytokines in immune regulation. Her work has defined mechanisms whereby key cytokines are induced by microbial products acting on innate cells to direct the development of protective immune responses to pathogens, and the regulation of such responses to prevent host damage by pathways which can also contribute to chronic infection such as in tuberculosis.

The development of an appropriate immune response to a specific pathogen is essential for its eradication. However, an uncontrolled immune response can result in collateral damage to the host. O’Garra pioneered studies revealing the role of cytokines in directing the immune response required to eradicate intracellular pathogens and identified key mechanisms whereby cytokines regulate this process. O’Garra first showed that the cytokine interleukin-10 (IL-10) inhibits macrophage and dendritic cell function, including the production of cytokines and their antigen presenting capacity which are critical for host protection and initiation of T cell responses. Following these landmark studies on IL-10, O’Garra went on to demonstrate that microbial products induce the production of the cytokines IL-12 and IL-18/IGIF by macrophages and dendritic cells which direct the development and maintenance of T helper 1 (Th1) responses critical for protection against intracellular pathogens. O’Garra’s findings that IL-10 inhibits IL-12 driven Th1 responses by direct action on macrophages and dendritic cells have stood the test of time, and underpin the mechanisms underlying many chronic infections. In keeping with this, in a landmark study published in 2010, O’Garra demonstrated a transcriptional signature of active tuberculosis dominated by type I interferon inducible genes, which she has shown contributes to chronic disease by induction of the suppressive cytokine IL-10 and inhibition of IL-12. O’Garra’s discoveries provide a unified framework explaining how cytokine responses determine the course of infection, with major implications for the development of new vaccines and strategies for intervention in infectious and inflammatory diseases.
Date: 1 October 2018, 12:00 (Monday, 0th week, Michaelmas 2018)
Venue: Kennedy Institute of Rheumatology, Headington OX3 7FY
Venue Details: Bernard Sunley Lecture Theatre
Speaker: Prof Anne O'Garra (Francis Crick Institute)
Organising department: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)
Organisers: Laura Sánchez Lazo (Kennedy Institute of Rheumatology), Professor Irina Udalova (Kennedy Institute of Rheumatology), Jo Silva (NDORMS), Wulf Forrester-Barker (University of Oxford, Nuffield Dept of Orthopaedics Rheumatology and Musculoskeletal Sciences)
Host: Prof Mark Coles (SENIOR RESEARCH FELLOW AND NEW GROUP LEADER)
Part of: Kennedy Institute Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Laura Sanchez Lazo