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Progression to Latent Infection Following Exposure to Mtb

ABSTRACT: These results were obtained in a controlled longitudinal experiment in which a group of rhesus macaques were exposed to a low dose of Mtb to study their progression to latent infection or active disease. Subsets of the animals were euthanized at scheduled time points, and granulomas taken from their lungs were assayed for gene expression. The clinical profiles associated with the animals following Mtb exposure revealed considerable variability, and we developed models for the disease trajectory for each subject using a Bayesian hierarchical B-spline approach. Disease severity estimates were derived from these fitted curves and included as covariates in linear models to identify genes significantly associated with disease progression. Our results demonstrate that the incorporation of clinical data increases the value of information extracted from the expression profiles and contributes to the identification of predictive biomarkers for TB susceptibility.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE56919 | GEO | 2014/04/19

SECONDARY ACCESSION(S): PRJNA244935

REPOSITORIES: GEO

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Progression to Latent Infection Following Exposure to Mtb

Project description:These results were obtained in a controlled longitudinal experiment in which a group of rhesus macaques were exposed to a low dose of Mtb to study their progression to latent infection or active disease. Subsets of the animals were euthanized at scheduled time points, and granulomas taken from their lungs were assayed for gene expression. The clinical profiles associated with the animals following Mtb exposure revealed considerable variability, and we developed models for the disease trajectory for each subject using a Bayesian hierarchical B-spline approach. Disease severity estimates were derived from these fitted curves and included as covariates in linear models to identify genes significantly associated with disease progression. Our results demonstrate that the incorporation of clinical data increases the value of information extracted from the expression profiles and contributes to the identification of predictive biomarkers for TB susceptibility. Samples from 21 animals were included in this study. 18 rhesus macaques were exposed to Mtb and euthanisized according to a pre-defined schedule, and at least two granulomas were extracted from their lungs during necropsy. The remaining three animals were healthy controls and samples represent control lung tissues. The samples were arrayed using an extended loop design with animals grouped according to similar clinical profiles. Biological replication is provided in the form of at least two granuloma samples per animal.

2014-04-19 | E-GEOD-56919 | biostudies-arrayexpress

Ultra-low dose aerosol infection provides an improved murine model of tuberculosis

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

Lymphoid function of the tuberculous granuloma

Project description:Induced lymphoid structures associated with pulmonary granulomas have been observed during TB in both humans and mice and could orchestrate host defense. In order to determine whether granulomas perform lymphoid functions, mice lacking secondary lymphoid organs (SLOs) were infected with Mycobacterium tuberculosis (MTB). As in wild type mice (WT), granulomas developed, MTB was controlled, and antigen-specific T cell responses including T central memory (TCM) cells were generated in the complete absence of SLOs. Moreover, T cell activation correlated with granuloma formation in these mice and TCM cells accumulated in lungs and participated in protection against secondary MTB infection. Lung granulomas may therefore represent tertiary lymphoid organs (TLOs) capable of priming robust T cell responses and mediating host defense during chronic MTB at the site of infection.

2010-12-22 | GSE15335 | GEO

Timecourse of doxycycline induction in bitransgenic MTB/TAN, MTB/TOM, and MTB/TWNT1 mice or monotransgenic MTB control mice

Project description:Genome-wide expression data can provide important insights into normal and pathological cellular processes. However, the ability to use gene expression data to quantitatively assess the activation state of a given signaling pathway or transcriptional network in a sensitive and specific manner remains an important unmet goal. We now describe a computational algorithm, energy-paired scoring (EPS), that satisfies these criteria by predicting pathway activity using gene-gene interactions within a pathway signature in a manner analogous to the estimation of energy generated by two charged particles, as described by Coulomb’s law. We demonstrate the ability of EPS to: quantitatively assess pathway activation levels in vivo and in vitro; accurately estimate the extent of pathway inhibition achieved by gene knockdown; sensitively detect crosstalk between endogenous signaling pathways in vivo; and accurately identify compounds capable of inhibiting selected signaling pathways. Our findings indicate that EPS can accurately predict pathway activity over a wide dynamic range based upon gene expression data sets derived from multiple profiling platforms, as well as different species, tissues and cell types in both in vitro and in vivo contexts Four timepoints (0h, 24h, 48h and 96h) with 3 replicates per timepoint of doxycycline induction for MTB (Control), MTB/TAN, MTB/TOM and MTB/TWNT1

2013-09-18 | E-GEOD-50969 | biostudies-arrayexpress

RNA sequencing of mammary glands from 55-day old control, MTB-200ba429, MTB-IGFIR, MTB-IGFIRba429 mice.

Project description:RNA was isolated from mammary glands from 55 day old control mice, mice overexpressing the miR-200b/200a/429 cluster in mammary epithelial cells (MTB-200ba429) mice overexpressing the IGF-IR transgene in mammary epithelial cells (MTB-IGFIR), and mice overexpressing both the miR-200b/200a/429 cluster and the IGF-IR transgene in mammary epithelial cells (MTB-IGFIRba429)

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System-wide identification of myeloid markers of TB disease and HIV-induced reactivation in the macaque model of Mtb infection and Mtb/SIV co-infection

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).

2022-09-23 | GSE213850 | GEO

Acetate Fermentation facilitates survival of Mtb when respiration is inhibited

Project description:Respiratory ATP-synthesis is at present the only known mechanism for ATP synthesis in Mtb. This makes Mtb particularly vulnerable to inhibition of respiratory ATP synthase inhibitors such as TMC207, a novel compound for treatment of tuberculosis. We now provide first evidence that Mtb possesses a pathway that is fermentative in nature that could compensate lack of respiratory ATP synthesis. We identified acetate as a fermentation product in Mtb. Production of acetate was mediated by phosphotransacetylase (Pta) and acetate kinase (AckA). In acetate fermenting Mtb cultures, ATP levels remained stable despite inhibition of respiratory ATP synthase. Deletion of the PtaAckA pathway in Mtb decreased ATP content and impaired survival. This study provides evidence that in Mtb substrate level phosphorylation can compensate lack of oxidative phosphorylation, and thus facilitates survival of Mtb in the absence of respiration. Acetate fermentation contributes to adaptation to respiration-limiting conditions, and plays an important role in the emerging field of fermentative metabolism of Mtb. We performed DNA microarray analysis to validate the reduction of oxygen concentration by comparing aerobic and hypoxic cultures. RNA was prepared from Mtb after two days of cultivation in aerobic and in hypoxic cultures. At each condition, Mtb were cultured in medium supplemented with glycerol and glucose. Labelled cDNA from three independent experiments was subjected to array analysis.

2012-12-31 | E-GEOD-35484 | biostudies-arrayexpress

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