Imperial College London

ProfessorAnneO'Garra

Faculty of MedicineNational Heart & Lung Institute

Chair in Infection Immunology
 
 
 
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a.ogarra

 
 
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Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
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268 results found

Cox LS, Alvarez-Martinez M, Wu X, Gabryšová L, Luisier R, Briscoe J, Luscombe NM, O'Garra Aet al., 2023, Blimp-1 and c-Maf regulate Il10 and negatively regulate common and unique proinflammatory gene networks in IL-12 plus IL-27-driven T helper-1 cells, Wellcome Open Research, Vol: 8, Pages: 403-403

<ns3:p><ns3:bold>Background: </ns3:bold>CD4<ns3:sup>+</ns3:sup> Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of <ns3:italic>Il10 </ns3:italic>and proinflammatory cytokines, including <ns3:italic>Ifng</ns3:italic> in Th1 cells.</ns3:p><ns3:p> <ns3:bold>Methods: </ns3:bold>We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted CD4<ns3:sup>+</ns3:sup> Th1 effector cells differentiated <ns3:italic>in vitro </ns3:italic>with IL-12 and IL-27 to produce <ns3:italic>Ifng </ns3:italic>and <ns3:italic>Il10, </ns3:italic>compared to control driven-CD4+ T cells<ns3:italic>. </ns3:italic>Data were integrated with analysis of active genomic regions from these Th1 cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of <ns3:italic>Il10 </ns3:italic>and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, <ns3:italic>Prdm1 </ns3:italic>(encoding Blimp-1)<ns3:italic> </ns3:italic>and <ns3:italic>Maf </ns3:italic>(encoding c-Maf)<ns3:italic>, </ns3:italic>in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell spec

Journal article

Wallis RS, O'Garra A, Sher A, Wack Aet al., 2023, Host-directed immunotherapy of viral and bacterial infections: past, present and future, NATURE REVIEWS IMMUNOLOGY, Vol: 23, Pages: 121-133, ISSN: 1474-1733

Journal article

Cox LS, Alvarez-Martinez M, Wu X, Gabryšová L, Luisier R, Briscoe J, Luscombe NM, O'Garra Aet al., 2023, Blimp-1 and c-Maf regulate  Il10 and negatively regulate common and unique proinflammatory gene networks in IL-12 plus IL-27-driven T helper-1 cells., Wellcome Open Res, Vol: 8, ISSN: 2398-502X

BACKGROUND: CD4 + Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells differentiated from mouse naive CD4 + T cells. METHODS: We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 + T cells from mouse spleens differentiated in vitro into Th1 effector cells with IL-12 and IL-27 to produce Ifng and Il10, compared to IL-27 alone which express Il10 only , or IL-12 alone which express Ifng and no Il10, or medium control driven-CD4 + T cells which do not express effector cytokines . Data were integrated with analysis of active genomic regions from these T cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of Il10 and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, Prdm1 (encoding Blimp-1) and Maf (encoding c-Maf) , in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell specific deletion of these transcription factors. RESULTS: We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce Il10 gene expression in IL-12 plus IL-27 differentiated mouse Th1 cells, but additionally directly negatively regulate key proinflammatory

Journal article

Tabone O, Verma R, Singhania A, Chakravarty P, Branchett WJ, Graham CM, Lee J, Trang T, Reynier F, Leissner P, Kaiser K, Rodrigue M, Woltmann G, Haldar P, O'Garra Aet al., 2021, Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 218, ISSN: 0022-1007

Journal article

Altmann MC, Rinchai D, Baldwin N, Toufiq M, Whalen E, Garand M, Kabeer BSA, Alfaki M, Presnell S, Khaenam P, Benitez AA, Mougin F, Thébault P, Chiche L, Jourde-Chiche N, Phillips JT, Klintmalm G, O'Garra A, Berry M, Bloom C, Wilkinson RJ, Graham CM, Lipman M, Lertmemongkolchai G, Bedognetti D, Thiebaut R, Kheradmand F, Mejias A, Ramilo O, Palucka K, Pascual V, Banchereau J, Chaussabel Det al., 2021, Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data, Nature Communications, Vol: 12, Pages: 1-19, ISSN: 2041-1723

As the capacity for generating large-scale molecular profiling data continues to grow, the ability to extract meaningful biological knowledge from it remains a limitation. Here, we describe the development of a new fixed repertoire of transcriptional modules, BloodGen3, that is designed to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome data. The construction of this repertoire is based on co-clustering patterns observed across sixteen immunological and physiological states encompassing 985 blood transcriptome profiles. Interpretation is supported by customized resources, including module-level analysis workflows, fingerprint grid plot visualizations, interactive web applications and an extensive annotation framework comprising functional profiling reports and reference transcriptional profiles. Taken together, this well-characterized and well-supported transcriptional module repertoire can be employed for the interpretation and benchmarking of blood transcriptome profiles within and across patient cohorts. Blood transcriptome fingerprints for the 16 reference cohorts can be accessed interactively via: https://drinchai.shinyapps.io/BloodGen3Module/.

Journal article

Moreira-Teixeira L, Stimpson PJ, Stavropoulos E, Hadebe S, Chakravarty P, Ioannou M, Aramburu IV, Herbert E, Priestnall SL, Suarez-Bonnet A, Sousa J, Fonseca KL, Wang Q, Vashakidze S, Rodriguez-Martinez P, Vilaplana C, Saraiva M, Papayannopoulos V, O'Garra Aet al., 2020, Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis, NATURE COMMUNICATIONS, Vol: 11

Journal article

Houlihan CF, Vora N, Byrne T, Lewer D, Kelly G, Heaney J, Gandhi S, Spyer MJ, Beale R, Cherepanov P, Moore D, Gilson R, Gamblin S, Kassiotis G, McCoy LE, Swanton C, Hayward A, Nastouli Eet al., 2020, Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers, LANCET, Vol: 396, Pages: E6-E7, ISSN: 0140-6736

Journal article

Moreira-Teixeira L, Tabone O, Graham CM, Singhania A, Stavropoulos E, Redford PS, Chakravarty P, Priestnall SL, Suarez-Bonnet A, Herbert E, Mayer-Barber KD, Sher A, Fonseca KL, Sousa J, Ca B, Verma R, Haldar P, Saraiva M, O'Garra Aet al., 2020, Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis, Nature Immunology, Vol: 21, Pages: 464-476, ISSN: 1529-2908

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.

Journal article

O'Garra A, Belkaid Y, Sharpe A, Kaech S, Cherry S, Passegue Eet al., 2020, <i>JEM</i> women in STEM: Unique journeys with a common purpose, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 217, ISSN: 0022-1007

Journal article

Branchett W, Stoelting H, Oliver R, Walker S, Puttur F, Gregory L, Gabrysova L, Wilson M, O'Garra A, Lloyd Cet al., 2020, A T cell-myeloid IL-10 axis regulates pathogenic IFN-γ-dependent immunity in a mouse model of type 2-low asthma, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 666-678.e9, ISSN: 0091-6749

BackgroundAlthough originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly severe disease. IL-10 regulates T helper (Th) cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthma are unclear. Objective: Determine how IL-10 regulates the balance of Th cell responses to inhaled allergen.MethodsAllergic airway disease (AAD) was induced in wild-type, IL-10 reporter and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice, by repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signalling were disrupted using blocking antibodies.ResultsRepeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10-producing FoxP3- effector CD4+ T cells in the lungs. Ablation of T cell-derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell-myeloid IL-10 axis resulted in elevated pulmonary monocyte-derived dendritic cell numbers and increased IFN-γ-dependent expression of CXCR3 ligands by airway macrophages, suggestive of a feedforward loop of Th1 cell recruitment. Augmented IFN-γ responses in the HDM AAD model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.ConclusionsIL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.

Journal article

Lloyd CM, Branchett WJ, O'Garra A, 2020, Transcriptomic analysis reveals diverse gene expression changes in airway macrophages during experimental allergic airway disease, Wellcome Open Research, Vol: 5

Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.

Journal article

Saraiva M, Vieira P, O'Garra A, 2020, Biology and therapeutic potential of interleukin-10, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 217, ISSN: 0022-1007

Journal article

Hewitt RJ, Graham C, Perez-Lloret J, Ghai PA, Ogger PP, Kemp SV, Molyneaux PL, Puttur F, Byrne AJ, Maher TM, O'Garra A, Lloyd CMet al., 2020, A Transcriptomic Profile of the Proximal Airway Epithelial-Immune Niche in Idiopathic Pulmonary Fibrosis, Virtual International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Branchett WJ, O'Garra A, Lloyd CM, 2020, Transcriptomic analysis reveals diverse gene expression changes in airway macrophages during experimental allergic airway disease., Wellcome Open Res, Vol: 5, ISSN: 2398-502X

Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs (CD11c + Siglec F + CD64 + CD45 + SSC hi) flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.

Journal article

Singhania A, Graham CM, Gabrysova L, Moreira-Teixeira L, Stavropoulos E, Pitt JM, Chakravarty P, Warnatsch A, Branchett WJ, Conejero L, Lin J-W, Davidson S, Wilson MS, Bancroft G, Langhorne J, Frickel E, Sesay AK, Priestnall SL, Herbert E, Ioannou M, Wang Q, Humphreys IR, Dodd J, Openshaw PJM, Mayer-Barber KD, Jankovic D, Sher A, Lloyd CM, Baldwin N, Chaussabel D, Papayannopoulos V, Wack A, Banchereau JF, Pascual VM, O'Garra Aet al., 2019, Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases, Nature Communications, Vol: 10, ISSN: 2041-1723

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

Journal article

Ouyang W, O'Garra A, 2019, IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation, IMMUNITY, Vol: 50, Pages: 871-891, ISSN: 1074-7613

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, MOSAIC Investigators, Moffatt MF, O'Garra A, Openshaw PJMet al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908

In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.

Journal article

Gabrysova L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, Hosking C, Perez-Mazliah D, Whicher C, Kannan Y, Potempa K, Wu X, Bhaw L, Wende H, Sieweke MH, Elgar G, Wilson M, Briscoe J, Metzis V, Langhorne J, Luscombe NM, O'Garra Aet al., 2019, c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells (vol 19, pg 497, 2018), NATURE IMMUNOLOGY, Vol: 20, Pages: 374-374, ISSN: 1529-2908

Journal article

Mann EH, Gabryšová L, Pfeffer PE, O'Garra A, Hawrylowicz CMet al., 2018, High-dose IL-2 skews a glucocorticoid-driven IL-17+IL-10+ memory CD4+ T cell response towards a single IL-10-producing phenotype, Journal of Immunology, Vol: 202, Pages: 684-693, ISSN: 1550-6606

Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4+ T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-γ+IL-10+ cells was also observed despite overall downregulation of IFN-γ production. These dexamethasone-driven IL-10+ cells, and predominantly the IL-17+IL-10+ double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2-dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10+ cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10+ T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17+IL-10+-coproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic.

Journal article

Singhania A, Wilkinson RJ, Rodrigue M, Haldar P, O'Garra Aet al., 2018, The value of transcriptomics in advancing knowledge of the immune response and diagnosis in tuberculosis, Nature Immunology, Vol: 19, Pages: 1159-1168, ISSN: 1529-2908

Blood transcriptomics analysis of tuberculosis has revealed an interferon-inducible gene signature that diminishes in expression after successful treatment; this promises improved diagnostics and treatment monitoring, which are essential for the eradication of tuberculosis. Sensitive radiography revealing lung abnormalities and blood transcriptomics have demonstrated heterogeneity in patients with active tuberculosis and exposed asymptomatic people with latent tuberculosis, suggestive of a continuum of infection and immune states. Here we describe the immune response to infection with Mycobacterium tuberculosis revealed through the use of transcriptomics, as well as differences among clinical phenotypes of infection that might provide information on temporal changes in host immunity associated with evolving infection. We also review the diverse blood transcriptional signatures, composed of small sets of genes, that have been proposed for the diagnosis of tuberculosis and the identification of at-risk asymptomatic people and suggest novel approaches for the development of such biomarkers for clinical use.

Journal article

Verma R, Singhania A, Graham C, Lee J, Woltmann G, O'Garra A, Haldar Pet al., 2018, Transcriptional Signature Identifies Phenotypic Heterogeneity of Human Tuberculosis Infection, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Gabrysova L, O'Garra A, 2018, Regulating the regulator: Bhlhe40 directly keeps IL-10 in check, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 215, Pages: 1767-1769, ISSN: 0022-1007

Journal article

Singhania A, Verma R, Graham CM, Lee J, Tran T, Richardson M, Lecine P, Leissner P, Berry MPR, Wilkinson RJ, Kaiser K, Rodrigue M, Woltmann G, Haldar P, O'Garra Aet al., 2018, A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection, Nature Communications, Vol: 9, ISSN: 2041-1723

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, OGarra A, Openshaw PJMet al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Journal article

Moreira-Teixeira L, Mayer-Barber K, Sher A, O'Garra Aet al., 2018, Type I interferons in tuberculosis: Foe and occasionally friend, Journal of Experimental Medicine, Vol: 215, Pages: 1273-1285, ISSN: 0022-1007

Tuberculosis remains one of the leading causes of mortality worldwide, and, despite its clinical significance, there are still significant 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. Transcriptional studies have uncovered a potential deleterious role for type I IFN in active tuberculosis. Since then, additional studies in human tuberculosis and experimental mouse models of M. tuberculosis infection support the concept that type I IFN promotes both bacterial expansion and disease pathogenesis. More recently, studies in a different setting have suggested a putative protective role for type I IFN. In this study, we 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.

Journal article

Gabrysova L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, Hosking C, Perez-Mazliah D, Whicher C, Kannan Y, Potempa K, Wu X, Bhaw L, Wende H, Sieweke MH, Elgar G, Wilson M, Briscoe J, Metzis V, Langhorne J, Luscombe NM, O'Garra Aet al., 2018, c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells, Nature Immunology, Vol: 19, Pages: 497-507, ISSN: 1529-2908

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.

Journal article

Benard A, Sakwa I, Schierloh P, Colom A, Mercier I, Tailleux L, Jouneau L, Boudinot P, Al-Saati T, Lang R, Rehwinkel J, Loxton AG, Kaufmann SHE, Anton-Leberre V, O'Garra A, Del Carmen Sasiain M, Gicquel B, Fillatreau S, Neyrolles O, Hudrisier Det al., 2018, B Cells Producing Type I IFN Modulate Macrophage Polarization in Tuberculosis, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 197, Pages: 801-813, ISSN: 1073-449X

Journal article

Esmail H, Lai R, Lesosky M, Wilkinson K, Graham C, Horswell S, Coussens A, Barry III CE, O'Garra A, Wilkinson RJet al., 2018, Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis, Proceedings of the National Academy of Sciences, Vol: 115, Pages: E964-E973, ISSN: 0027-8424

The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [18F]-fluoro-2-deoxy-D-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1–infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fcγ receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.

Journal article

Moreira-Teixeira L, Redford PS, Stavropoulos E, Ghilardi N, Maynard CL, Weaver CT, Freitas do Rosario AP, Wu X, Langhorne J, O'Garra Aet al., 2017, T Cell-Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection, JOURNAL OF IMMUNOLOGY, Vol: 199, Pages: 613-623, ISSN: 0022-1767

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. CD4+ T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C+ monocytes. However, after day 21 postinfection, IL-10–expressing T cells were also highly represented. Notably, mice deficient in T cell–derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL-10–competent mice, indicating a major role for T cell–derived IL-10 in TB susceptibility. IL-10–expressing cells were detected among both CD4+ and CD8+ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN-γ and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4+ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10–induced TB susceptibility.

Journal article

Lin JW, Sodenkamp J, Cunningham D, Deroost K, Tshitenge TC, McLaughlin S, Lamb TJ, Spencer-Dene B, Hosking C, Ramesar J, Janse CJ, Graham C, O'Garra A, Langhorne Jet al., 2017, Signatures of malaria-associated pathology revealed by high-resolution whole-blood transcriptomics in a rodent model of malaria., Scientific Reports, Vol: 7, ISSN: 2045-2322

The influence of parasite genetic factors on immune responses and development of severe pathology of malaria is largely unknown. In this study, we performed genome-wide transcriptomic profiling of mouse whole blood during blood-stage infections of two strains of the rodent malaria parasite Plasmodium chabaudi that differ in virulence. We identified several transcriptomic signatures associated with the virulent infection, including signatures for platelet aggregation, stronger and prolonged anemia and lung inflammation. The first two signatures were detected prior to pathology. The anemia signature indicated deregulation of host erythropoiesis, and the lung inflammation signature was linked to increased neutrophil infiltration, more cell death and greater parasite sequestration in the lungs. This comparative whole-blood transcriptomics profiling of virulent and avirulent malaria shows the validity of this approach to inform severity of the infection and provide insight into pathogenic mechanisms.

Journal article

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