Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
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ABSTRACT:
ORGANISM(S): Macaca fascicularis
PROVIDER: GSE200151 | GEO | 2022/04/07
REPOSITORIES: GEO
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Project description:Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
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Project description:The progression of human tuberculosis (TB) to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome-wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous TB granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl-CoA synthetase long-chain family member 1 and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols and lactosylceramide, which implicated low-density lipoprotein-derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human TB granuloma to caseation correlates with pathogen-mediated dysregulation of host lipid metabolism.
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Project description:Neutrophils are implicated in the pathogenesis of tuberculosis (TB), a disease caused by Mycobacterium tuberculosis infection, but the mechanisms by which they promote disease are not fully understood. Neutrophils can express cytokines that influence TB progression, and so we compared neutrophil and T-cell expression of the Th1 cytokines IFNγ and TNF, the Th2 cytokine IL-4, and regulatory cytokine IL-10 in M. tuberculosis-infected macaques to determine if neutrophil cytokine expression contributes to dysregulated immunity in TB. We found that peripheral blood neutrophils produced cytokines after stimulation by mycobacterial antigens and inactive and viable M. tuberculosis. M. tuberculosis antigen-stimulated neutrophils inhibited antigen-specific T-cell IFNγ production. In lung granulomas, neutrophil cytokine expression resembled T-cell cytokine expression, and although there was histologic evidence for neutrophil interaction with T cells, neutrophil cytokine expression was not correlated with T-cell cytokine expression or bacteria load. There was substantial overlap in the spatial arrangement of cytokine-expressing neutrophils and T cells, but IL-10-expressing neutrophils were also abundant in bacteria-rich areas between caseum and epithelioid macrophages. These results suggest that neutrophils contribute to the cytokine milieu in granulomas and may be important immunoregulatory cells in TB granulomas.
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Project description:Heligmosomoides polygyrus larvae induce a strong intestinal granuloma response within their murine host, which has been associated with resistance. Immune cells, mostly alternatively activated macrophages and eosinophils, accumulate around the tissue encysted parasites to immobilize and damage/kill developing worms. In a one dose (bolus) experimental infection, infected C57Bl/6 mice are unable to clear parasites which results in chronic infection with high worm burdens. However, using a frequent dose trickle model of infection, we, like others, have found that C57Bl/6 mice can clear infection. The nanoString data included here measure the expression of key myeloid genes within the granuloma tissue from bolus and trickle infections. Our results highlight the importance of the granuloma in the host’s ability to clear H. polygyrus and emphasise the need to study this key tissue in more depth, rather than using correlates such as general intestinal or systemic responses.
2022-12-28 | GSE164319 | GEO
Project description:The role of neutrophils in tuberculosis (TB), and whether neutrophils express granzyme B (grzB), a pro-apoptotic enzyme associated with cytotoxic T cells, is controversial. We examined neutrophils in peripheral blood (PB) and lung granulomas of Mycobacterium tuberculosis-infected cynomolgus macaques and humans to determine whether mycobacterial products or pro-inflammatory factors induce neutrophil grzB expression. We found large numbers of grzB-expressing neutrophils in macaque and human granulomas and these cells contained more grzB+ granules than T cells. Higher neutrophil, but not T cell, grzB expression correlated with increased bacterial load. Although unstimulated PB neutrophils lacked grzB expression, grzB expression increased upon exposure to M.tuberculosis bacilli, M.tuberculosis culture filtrate protein or lipopolysaccharide from Escherichia coli. Perforin is required for granzyme-mediated cytotoxicity by T cells, but was not observed in PB or granuloma neutrophils. Nonetheless, stimulated PB neutrophils secreted grzB as determined by enzyme-linked immunospot assays. Purified grzB was not bactericidal or bacteriostatic, suggesting secreted neutrophil grzB acts on extracellular targets, potentially enhancing neutrophil migration through extracellular matrix and regulating apoptosis or activation in other cell types. These data indicate mycobacterial products and the pro-inflammatory environment of granulomas up-regulates neutrophil grzB expression and suggests a previously unappreciated aspect of neutrophil biology in TB.
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Project description:The feasibility of longitudinal metastatic biopsies for gene expression profiling in breast cancer is unexplored. Dynamic changes in gene expression can potentially predict efficacy of targeted cancer drugs. Patients enrolled in a phase III trial of metastatic breast cancer with sunitinib combined with docetaxel (SU+DOC) versus docetaxel alone (DOC) were offered to participate in a translational substudy comprising longitudinal fine needle aspiration biopsies (FNAB) and positron emission imaging before (T1) and two weeks after start of treatment (T2). Aspirated tumor material was used for microarray analysis, and treatment-induced changes (T2 versus T1) in gene expression and standardized uptake values were investigated. Twenty-one patients were included in the docetaxel ± sunitinib trial at Karolinska and 18 of them agreed to participate in the substudy. Of the 18 women enrolled, 8 were randomly assigned to SU+DOC and 10 to DOC. Metastatic FNAB were carried out in 17 of the 18 patients at both time points with no complications reported. Representative tumor material, sufficient for RNA extraction was obtained in 15 patients at T1 and 14 patients at T2. Matched samples both at T1 and T2 were obtained for 14 subjects, 7 in each arm. The main objective was to determine whether gene expression profiling is feasible using sequential, intra-patient FNAB. Secondary objectives were to identify potential biomarkers of early response by gene expression and/or functional imaging and to explore drug action in vivo by changes in gene expression. A Karolinska substudy of the docetaxel ± sunitinib phase III clinical trial utilising sequential metastatic fine needle aspiration biopsies (FNAB) and 18-F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT). In brief, the randomized docetaxel ± sunitinib trial compared sunitinib combined with docetaxel (SU+DOC) versus docetaxel alone (DOC), as first line therapy in patients with HER2 negative metastatic breast cancer. Patients in the exploratory substudy were subjected to baseline FDG PET/CT assessment, followed by FNAB of one tumor lesion prior to start of treatment (Time point T1). FDG PET/CT and FNAB were repeated at Day 14 ± 1 (Time point T2) when sunitinib has achieved steady state.
2015-04-14 | E-GEOD-54323 | biostudies-arrayexpress
Project description:Control of Mycobacterium tuberculosis infection requires generation of T cells that migrate to granulomas, complex immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in pulmonary granulomas, bronchoalveolar lavage and blood of Mtb-infected rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was among the top genes that was upregulated in both CD4 and CD8 granuloma T cells and independent of bacterial loads. Transcriptomic profiling of lung T cells from Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and effector molecule expression. Moreover, in mice CD30 expression on CD4 T cells is required for survival of Mtb infection. These results show the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is critical for the generation of protective T cell responses against Mtb infection.
2023-03-24 | GSE228113 | GEO
Project description:Control of Mycobacterium tuberculosis infection requires generation of T cells that migrate to granulomas, complex immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in pulmonary granulomas, bronchoalveolar lavage and blood of Mtb-infected rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was among the top genes that was upregulated in both CD4 and CD8 granuloma T cells and independent of bacterial loads. Transcriptomic profiling of lung T cells from Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and effector molecule expression. Moreover, in mice CD30 expression on CD4 T cells is required for survival of Mtb infection. These results show the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is critical for the generation of protective T cell responses against Mtb infection.
2023-03-22 | GSE227653 | GEO
Project description:We hypothesised that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a non-infectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared three primary human cell culture models at the whole transcriptome level, and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified twelve intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.
2021-05-15 | GSE174443 | GEO
Project description:Granulomas function in humans during tuberculosis by focusing production of host antimicrobial factors against the causative bacterial agent Mycobacterium tuberculosis to contain infection. We show that mice unable to produce nitric oxide –itself an important antimicrobial molecule- demonstrate functional granulomas in the lung able to control infection after dermal infection. Disease in the lung was activated by administration of neutralising antibody against either TNF-α, which disrupted granuloma integrity, or INF-γ, which resulted in development of caseous necrosis within granulomas reminiscent of active human tuberculosis. In the latter case, the serpin protease inhibitor serpinb3a and its target protease, cathepsin G are highly expressed in cells local to necrotic regions in granulomas and serpinb3a induces necrosis of infected macrophages independently of cathepsin G binding. Therefore a single host protein is capable of inducing necrosis and bacterial growth during intracellular infection.
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