Gene expression profiling identifies a gene signature that predicts progression to active tuberculosis several years before disease onset
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112104 | GEO | 2020/02/25
REPOSITORIES: GEO
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Project description:Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators).
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2021-04-23 | GSE163498 | GEO
Project description:Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects approximately one-fourth of the world’s population. The majority of infected persons are asymptomatic, but latent TB infection (LTBI) can progress to active clinical disease in 5-10% of infected individuals. The immune mechanisms that govern progression from latent to active pulmonary TB (PTB) remain poorly defined. An in-depth understanding of immune factors correlating with TB disease, as well as protection during TB, is necessary for developing new immunotherapies to promote immune control of Mtb. Experimentally Mtb-infected non-human primates (NHP) mirror the disease progression and pathology observed in humans and can recapitulate both PTB and LTBI. In the present study, we have characterized the lung immune landscape in NHPs with LTBI and PTB using high-throughput technologies including single-cell RNA sequencing (scRNA-seq) and Time of flight cytometry (CyTOF). We show that the three defining features of PTB in macaque lungs are the influx of plasmacytoid DCs (pDCs), an Interferon (IFN)-exhibiting alveolar macrophage population and predominant activated T cell responses. These features contribute to uncontrolled inflammation and disease without mediating Mtb control. In contrast, a CD27+ Natural killer (NK) cell subset accumulated in the lungs of LTBI macaques and in circulation in individuals with LTBI, thus providing novel insights into the protective lung landscape that functions during TB latency. A comprehensive understanding of the lung immune landscape as described here will improve our overall understanding of TB disease immunopathogenesis and provide novel targets for design of new therapies and vaccines for TB control.
2020-12-23 | GSE149758 | GEO
Project description:Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the mouse TB model and show that ULD infection recapitulates key features of human TB.
2020-11-06 | GSE158807 | GEO
Project description: Not available
| S-EPMC8182229 | biostudies-literature
Project description:Mycobacterium tuberculosis (Mtb) infects a quarter of the world’s population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at cellular level is crucial to design better strategies to control TB. We have employed single-cell RNA-seq approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show enrichment of type I IFN responsive phenotypes among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We have identified Ly6A as a novel lymphoid cell activation marker and validated its upregulation in activated lymphoid cells post Mtb infection. The cross analysis of type I IFN signature in human TB infected peripheral blood samples further validates our results. These findings significantly contribute toward understanding and characterizing the transcriptional parameters at single-cell depth in a highly relevant and reproducible mouse model of TB.
2022-06-24 | GSE200639 | GEO
Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is an exquisitely adapted human pathogen capable of surviving for decades in the lungs of immune competent individuals in absence of disease. The World Health Organization estimates that 2 billion people have latent TB infection (LTBI), defined by positive immunologic response to Mtb antigens with no clinical signs of disease. A better understanding of host and pathogen determinants of LTBI and subsequent reactivation would benefit TB control efforts. Animal models of LTBI have been hampered mainly by an inability to achieve complete bacillary clearance. We have characterized a rabbit model of LTBI in which, similar to most humans, complete clearance of pulmonary Mtb infection and pathology occurs spontaneously. The evidence that Mtb-CDC1551-infected rabbits achieve LTBI, rather than sterilization, is based on the ability of the bacilli to be reactivated following immune suppression. The microarray experiments involves comparison of: 1) Changes in rabbit gene expression between Mtb-CDC1551 infected and uninfected animals at 2,4,8 and 12 weeks post infection. New Zealand White rabbits were infected with Mtb CDC1551 at 3.5log10 (on day 0). Lung tissue from Mtb-infected rabbits were isolated from uninfected (control) and at 2, 4, 8 and 16 weeks post infection and used for total RNA extraction. Total rabbit lung RNA was used for microarray analysis to determine infection induced changes in host gene expression.
2012-07-10 | E-GEOD-39219 | biostudies-arrayexpress
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. Mice were infected with Mtb and treatment with PZA was started at 28 days post-infection. At 42 days and 63 days post-infection, group of animals were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. Mtb-infected, untreated animals served as controls.
2013-06-28 | E-GEOD-48027 | biostudies-arrayexpress
Project description:Tuberculosis (TB) is the deadliest infectious disease worldwide. One obstacle hindering the elimination of TB is our lack of understanding of host-pathogen interactions. Exosomes, naturally loaded with microbial molecules, are circulating markers of TB. Changes in the host protein composition of exosomes from Mycobacterium tuberculosis (Mtb)-infected cells have not been described, can contribute to our understanding of the disease process, and serve as a direct source of biomarkers or as capture targets to enrich for exosomes containing microbial molecules. Here, the protein composition of exosomes from Mtb-infected and uninfected THP-1-derived macrophages was evaluated by tandem-mass-spectrometry and differences in protein abundances were assessed. Our results show that infection with Mtb leads to significant changes in the protein composition of exosomes. Specifically, 41 proteins were significantly more abundant in exosomes from Mtb-infected cells; 63% of these were predicted to be membrane associated. Thus, we used a novel biotinylation strategy to verify protein localization, and confirmed the localization of some of these proteins in the exosomal membrane. Our findings reveal another important scenario where Mtb could be influencing changes in host cells that unveil new features of the host-pathogen interaction and may also be exploited as a source of biomarkers for TB.
2018-08-06 | PXD010659 | Pride
Project description:To define mechanisms that underlie progression of Mycobacterium tuberculosis (M.tb) infection to active tuberculosis (TB), we followed M.tb-infected adolescents longitudinally. Those who ultimately developed TB disease (“progressors”) were compared with matched controls, who remained healthy. Whole blood transcriptomic and plasma proteome analyses showed sequential modulation of immunological processes: type I/II interferon signalling and complement cascade were elevated 18 months before TB diagnosis, while changes in myeloid inflammation and lymphoid cell, monocyte and neutrophil gene modules occurred more proximally to TB disease. Analysis of gene expression in purified T cells revealed early suppression of Th17 responses in progressors. This was confirmed in an adult BCG re-vaccination cohort, where expression of interferon response genes in blood was associated with suppression of IL-17 expression by BCG-specific CD4 cells. We concluded that sequential inflammatory dynamics and immune alteration precede TB disease manifestation, with important implications for developing diagnostics, vaccines and host-directed therapies for TB.
2017-10-17 | GSE103147 | GEO