Biology subjects

O'Garra, A.

Publications and source records attributed to O'Garra, A..

9 recordsLinked to original sources

bioRxiv2026

Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammatory pathology in HIV associated TB meningitis

Immune dysregulation contributes to death and disability in tuberculous meningitis. People living with HIV have the least evidence that anti-inflammatory therapy improves the poor outcome. Improving therapy relies on a more refined understanding of the host immune response. Single-cell RNA sequencing of 188,983 CSF cells from 25 adults with HIV-associated TBM revealed a predominance of cytotoxic CD8 T cells with low cytokine expression. In microbiologically-confirmed TBM, there was greater cytotoxicity in T, NK and {gamma}{delta} cells, and higher type 1 interferon stimulation in T and B lymphocytes. Neutrophils expressed markers suggesting heightened cytokine stimulation, enhanced effector function, and IL-8-mediated neutrophil recruitment. In a longitudinal cohort, type 1 interferon signaling increased in blood and CSF following treatment initiation. Overall, findings indicate a hyper-inflammatory immune response in the CSF of HIV-associated TBM patients characterised by an accumulation of granzyme-rich cytotoxic CD8 T cells, highly activated neutrophils and host-detrimental type 1 interferon signaling.

immunology↗

bioRxiv2026

Immune signatures of protection and progression in the airways of recent human tuberculosis household contacts

Whilst the majority of individuals infected with M. tuberculosis control the infection and remain asymptomatic, only 5-10% progress to active tuberculosis (TB)1. Previous or current infection with M. tuberculosis is detected using antigen-specific interferon (IFN)-{gamma} release assays (IGRA), which cannot identify those who will remain healthy or progress to active TB1. However, 18F-Fluorodeoxyglucose positron emission-computed tomography (PET-CT) can detect increased immune cell metabolic activity in lung parenchyma and intrathoracic lymph nodes associated with infection2. The local early immune factors dictating protection or disease progression have not been defined. To address this, we interrogated the airway immune response at single cell resolution in bronchoalveolar lavage (BAL) from extensively clinically characterised recent household contacts of TB patients, who either controlled the infection or progressed to TB disease. Using unbiased analysis of bulk and scRNA-seq of BAL samples, we define type I IFN-dependent and -independent neutrophil signatures in active TB patients and contacts that progressed to TB. We additionally report an inverse relationship between airway neutrophils and T cells, with T cells showing signatures of exhaustion, cytotoxicity and cell death in progressors and TB patients with a neutrophil dominated airway profile. Conversely, T cell signatures of protection in contacts who remained healthy were dominated by genes related to regulation, quiescence and a stem-like profile. We show that both the inflammatory neutrophil signature of TB progression and the stem-like T cell signature of non-progressors from human airways were recapitulated in scRNA-seq data from non-human primate (NHP) granulomas, associated with disease or immune protection, respectively. Our findings from early human airway responses in TB contacts reveal genes, pathways and cell states that may dictate infection outcome and inform strategies for host-directed therapy and vaccine studies.

immunology↗

bioRxiv2023

Blimp-1 and c-Maf regulate common and unique gene networks to protect against distinct pathways of pathobiont-induced colitis

Intestinal immune responses to commensals and pathogens are controlled by IL-10 to avoid intestinal immune pathology. We show that the transcription factors Blimp-1 (Prdm-1) and c-Maf are co-dominant regulators of Il10 in Foxp3+ regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion of Prdm-1, Maf or the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficient Prdm1fl/flMaffl/flCd4Cre mice infected with Helicobacter hepaticus developed severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), while Prdm1fl/flCd4Cre and Maffl/flCd4Cre mice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infected Maffl/flCd4Cre mice showed increased Il17a expression and an accompanying increase in granulocytes and myeloid cells, which was less marked in Prdm1fl/flMaffl/flCd4Cre mice, with increased T cell-myeloid-neutrophil interactions inferred from scRNA-seq analysis and confirmed by immunofluorescent analysis of colon sections. Genes over-expressed in human IBD showed differential expression in the LPL from infected mice in the absence of Prdm1 or Maf, revealing potential pathobiologic mechanisms of human disease.

immunology↗

bioRxiv2020

Transcriptomic characterization of tuberculous sputum reveals a host Warburg effect and microbial cholesterol catabolism

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum yet cannot easily be modeled. We applied one-step RNA-Sequencing to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis (Mtb). In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses and a metabolic shift towards glycolysis was observed in the host. Amongst all bacterial sequences in the sputum, only less than 1.5% originated from Mtb and its abundance is associated with HIV-1 coinfection status. The transcriptome of sputum Mtb more closely resembled aerobic replication and was characterized by evidence of cholesterol utilization, zinc deprivation and reduced expression of the virulence-associated PhoP regulon. Our study provides a comprehensive analysis of the transcriptional landscape associated with infectious sputum and demonstrates the feasibility of applying advanced sequencing technology to readily accessible pathological specimens in the study of host-pathogen adaptation.

microbiology↗

bioRxiv2019

A Transcriptome Fingerprinting Assay for Clinical Immune Monitoring

BackgroundWhile our understanding of the role that the immune system plays in health and disease is growing at a rapid pace, available clinical tools to capture this complexity are lagging. We previously described the construction of a third-generation modular transcriptional repertoire derived from genome-wide transcriptional profiling of blood of 985 subjects across 16 diverse immunologic conditions, which comprises 382 distinct modules.\n\nResultsHere we describe the use of this modular repertoire framework for the development of a targeted transcriptome fingerprinting assay (TFA). The first step consisted in down-selection of the number of modules to 32, on the basis of similarities in changes in transcript abundance and functional interpretation. Next down-selection took place at the level of each of the 32 modules, with each one of them being represented by four transcripts in the final 128 gene panel. The assay was implemented on both the Fluidigm high throughput microfluidics PCR platform and the Nanostring platform, with the list of assays target probes being provided for both. Finally, we provide evidence of the versatility of this assay to assess numerous immune functions in vivo by demonstrating applications in the context of disease activity assessment in systemic lupus erythematosus and longitudinal immune monitoring during pregnancy.\n\nConclusionsThis work demonstrates the utility of data-driven network analysis applied to large-scale transcriptional profiling to identify key markers of immune responses, which can be downscaled to a rapid, inexpensive, and highly versatile assay of global immune function applicable to diverse investigations of immunopathogenesis and biomarker discovery.

immunology↗

bioRxiv2019

A Novel Repertoire of Blood Transcriptome Modules Based on Co-expression Patterns Across Sixteen Disease and Physiological States

As the capacity for generating large scale 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. It is meant to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome profiling data. It is supported by customized resources, which include analysis workflows, fingerprint grid plots data visualizations, interactive web applications providing access to a vast number of module-specific functional profiling reports, reference transcriptional profiles and give users the ability to visualize of changes in transcript abundance across the modular repertoire at different granularity levels. A use case focusing on a set of six modules comprising interferon-inducible genes is also provided. Altogether we hope that this resource will also serve as a framework for improving over time our collective understanding of the immunobiology underlying blood transcriptome profiling data.

immunology↗

bioRxiv2018

Glycosylation-dependent modulation of the lL-2 signaling axis determines Th17 differentiation and IL-10 production

Metabolism plays an essential role in shaping T helper (Th) cell responses including the production of pro-inflammatory cytokines, however the effects on IL-10 have not been investigated. We show that the glucose analogue 2-deoxyglucose (2DG) specifically inhibits Th1 and Th2 cell differentiation and accompanying IL-10 production. In contrast, 2DG promotes IL-17A production by Th17 cells, even in the presence of IL-2 known to limit Th17 differentiation, whilst totally abrogating the production of IL-10. Notably, rather than inhibiting glycolysis, 2DG acts through the inhibition of glycosylation, which is critical for IL-2R surface expression and downstream signaling in both mouse and man. Strikingly, IL-2 is essential for IL-10 production by Th17 cells, in contrast to its inhibitory effect on the production of IL-17A. Our study reveals a previously unappreciated, anti-inflammatory role for IL-2 in Th17 cell production of IL-10 and thus identifies a novel mechanism to limit Th17 pathogenicity.

immunology↗

bioRxiv2018

Differential expression of an alternative splice variant of IL-12Rβ1 impacts early dissemination in the mouse and associates with disease outcome in both mouse and humans exposed to tuberculosis

Experimental mouse models of TB suggest that early events in the lung impact immunity. Early events in the human lung in response to TB are difficult to probe and their impact on disease outcome is unknown. We have shown in mouse that a secreted alternatively-spliced variant of IL-12R{beta}1, lacking the transmembrane domain and termed {Delta}TM-IL-12R{beta}1, promotes dendritic cell migration to the draining lymph node, augments T cell activation and limits dissemination of M. tuberculosis (Mtb). We show here that CBA/J and C3H/HeJ mice (both highly susceptible to Mtb) express higher levels of {Delta}TM-IL-12R{beta}1 than resistant C57BL6 mice and limit early dissemination of Mtb from the lungs. Both CD11c+ cells and T cells express {Delta}TM-IL-12R{beta}1 in humans, and mice unable to make {Delta}TM-IL-12R{beta}1 in either CD4 or CD11c expressing cells permit early dissemination from the lung. Analysis of publically available blood transcriptomes indicates that pulmonary TB is associated with high {Delta}TM-IL-12R{beta}1 expression and that of all IL-12 related signals, the {Delta}TM-IL-12R{beta}1 signal best predicts active disease. {Delta}TM-IL-12R{beta}1 expression reflects the heterogeneity of latent TB infection and has the capacity to discriminate between latent and active disease. In a new Chinese TB patient cohort, {Delta}TM-IL-12R{beta}1 effectively differentiates TB from latent TB, healthy controls and pneumonia patients. Finally, {Delta}TM-IL-12R{beta}1 expression drops in drug-treated individuals in the UK and China where infection pressure is low. We propose that {Delta}TM-IL-12R{beta}1 regulates early dissemination from the lung and that it has diagnostic potential and provides mechanistic insights into human TB.

immunology↗

bioRxiv2017

A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection

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 information from the entire transcriptome, which includes over-abundance of type I interferon-inducible genes and under-abundance 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 methods targeting gene selection across multiple discriminant modules can improve development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.

immunology↗