Cytomegalovirus as a risk factor for exacerbation of Mycobacterium tuberculosis: development of a Mtb-CMV mouse model infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315842 | GEO | 2026/01/12
REPOSITORIES: GEO
Similar Datasets
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:Transcriptional profiling of aortic sinus atherosclerotic plaque macrophages obtained by laser capture microdissection from male ApoE deficient mice infected with 5x10(5) cfu serotype 4 Streptococcus pneumoniae via intranasal instillation (n=9) as compared with mice mock infected with PBS (n=11). Mice were culled 2 weeks post infection/mock infection.
2022-02-15 | E-MTAB-11462 | biostudies-arrayexpress
Project description:Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a prospective case–control analysis to identify the drivers of immune activation in infants and found cytomegalovirus (CMV) stimulated IFN-γ-expressing cells to be associated with CD8+ T cell activation (Spearman’s rho r = 0.241, p <0.0001). Among 49 infants who developed incident TB disease and 129 matched controls who remained healthy we found that CMV and Epstein–Barr virus (EBV) specific IFN-γ responses were associated with increased risk of developing TB (Fisher’s Exact Test, p=0.049, OR 2.14, 95% CI 1.03-4.47), and associated with a shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.012). T cell activation and CMV are associated with lower mycobacterial antigen-specific immune responses following immunization with Bacille Calmette-Guerin (BCG) and MVA85A, suggesting that increased susceptibility to TB in infants with virus infection may, in part, be due to poor responsiveness to vaccination. Understanding of the causes and impact of T cell activation could transform strategies used to protect against TB disease.
2018-12-05 | GSE98550 | GEO
Project description:Current antibiotic regimen to treat tuberculosis (TB) is ineffective in fully eliminating the bacterial load and in alleviating disease pathology. We examined the usefulness of a phosphodiesterase-4 inhibitor (CC-11050) as an adjunctive to anti-TB drug Isoniazid (INH) to improve the outcome of treatment in a rabbit model of active pulmonary TB. Control of Mycobacterium tuberculosis (Mtb) growth, disease pathology and the global transcriptional response in Mtb-infected lungs of rabbits with or without CC-11050 treatment were studied. The microarray experiments involves comparison of changes in gene expression between uninfected and Mtb-HN878 infected (Untreated) or CC-11050 treated rabbit lungs at 8 weeks post-treatment, starting at 4 weeks of infection (i.e, 12 weeks post infection).
2015-12-21 | GSE74687 | GEO
Project description:Tuberculosis (TB) remains the world’s top infectious killer. Understanding how immune mediators determine the outcome of Mycobacterium tuberculosis infection could facilitate the design of better therapies against this devastating disease. GM-CSF mediates protective immunity against TB but the underlying mechanisms remain elusive. To determine the molecular mechanisms underlying the protective role of GM-CSF during M. tuberculosis infection we performed RNA-sequencing analyses of whole blood and lung samples obtained from C57Bl/6 mice infected with HN878 and treated with anti-GM-CSF monoclonal antibody or isotype control. Uninfected mice were also treated and used as uninfected controls. Three weeks post-infection, whole blood and lungs were harvested from each individual mouse and processed for RNA-sequencing. Transcriptomic analyses revealed that during M. tuberculosis infection GM-CSF regulates the expression of genes associated with neutrophil recruitment and activation and type I IFN-inducible genes, which have been previously associated with TB pathogenesis. Further mechanistical studies showed that disease exacerbation driven by GM-CSF blockade during M. tuberculosis infection was type I IFN and neutrophil-dependent and that over-activation of neutrophils by type I IFN induced NET formation at the site of infection. NETs were also found in necrotic lung lesions from patients with pulmonary TB and type I IFN-driven NET formation correlated with increased disease susceptibility in different mouse models of TB. Our findings reveal an important immune network that may play a central role in determining TB outcome.
2020-09-07 | GSE141192 | GEO
Project description:Tuberculosis (TB) remains the world’s top infectious killer. Understanding how immune mediators determine the outcome of Mycobacterium tuberculosis infection could facilitate the design of better therapies against this devastating disease. GM-CSF mediates protective immunity against TB but the underlying mechanisms remain elusive. To determine the molecular mechanisms underlying the protective role of GM-CSF during M. tuberculosis infection we performed RNA-sequencing analyses of whole blood and lung samples obtained from C57Bl/6 mice infected with HN878 and treated with anti-GM-CSF monoclonal antibody or isotype control. Uninfected mice were also treated and used as uninfected controls. Three weeks post-infection, whole blood and lungs were harvested from each individual mouse and processed for RNA-sequencing. Transcriptomic analyses revealed that during M. tuberculosis infection GM-CSF regulates the expression of genes associated with neutrophil recruitment and activation and type I IFN-inducible genes, which have been previously associated with TB pathogenesis. Further mechanistical studies showed that disease exacerbation driven by GM-CSF blockade during M. tuberculosis infection was type I IFN and neutrophil-dependent and that over-activation of neutrophils by type I IFN induced NET formation at the site of infection. NETs were also found in necrotic lung lesions from patients with pulmonary TB and type I IFN-driven NET formation correlated with increased disease susceptibility in different mouse models of TB. Our findings reveal an important immune network that may play a central role in determining TB outcome.
2020-09-07 | GSE141205 | GEO
Project description:Treatment of chronic inflammatory diseases with tumor necrosis factor alpha antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared to infected untreated animals. The microarray experiments involves comparison of changes in gene expression between Mtb-HN878 infected and Etanercept treated and untreated rabbit lungs at 4 and 8 weeks post-treatment, starting at 4 weeks post-infection.
2014-01-28 | GSE54442 | GEO
Project description:Treatment of chronic inflammatory diseases with tumor necrosis factor alpha antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared to infected untreated animals. The microarray experiments involves comparison of changes in gene expression between Mtb-HN878 infected and Etanercept treated and untreated rabbit lungs at 4 and 8 weeks post-treatment, starting at 4 weeks post-infection. New Zealand White rabbits were infected with Mtb HN878 at about 3.2log10 (on day 0). One group of rabbits were treated with Etanercept, starting at 4 weeks post-infection, for 4 or 8 weeks. Total RNA from lung tissues of treated and untreated animals were isolated at 4 and 8 weeks post treatment and used for microarray gene expression analysis.
2014-01-28 | E-GEOD-54442 | biostudies-arrayexpress
Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. Serum samples collected from adult patients with suspected tuberculosis during a multi-site study was used to probe whole proteome microarrays. Subject recruitment was conducted under uniform protocols approved by the institutional ethics committee at each site. Final diagnosis of active TB was based on positive M. tuberculosis culture results. The active TB patients were further subdivided into smear-positive and negative disease based on results of Ziehl-Neelsen staining of sputum smears for acid fast bacilli. Active TB was excluded as a diagnosis (Non-TB Disease [NTBD] patients) based on having negative M. tuberculosis culture and smear results and on having an alternate diagnosis. All subjects were presumably negative for HIV infection given the very low incidence of HIV infection in the study sites. Sera from 169 TB and 242 NTBD patients were selected for microarray probing. The control sera (n = 14) which was used to generate negative control distribution for each protein were negative to latent M. tuberculosis infection, as indicated by negative results to tuberculin skin test.
2012-07-05 | E-GEOD-30722 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (M. tb), the cause of tuberculosis (TB), utilizes the blood circulation to spread systemically and establish infection, and the risk of developing active TB (pulmonary and extrapulmonary) is significantly increased in individuals infected with human immunodeficiency virus (HIV). In this work, we have used DNA microarray analysis to investigate the transcriptome of M. tb replicating in human whole blood from both HIV-negative and HIV-positive donors compared to M. tb grown in Middlebrook 7H9 broth media in order to identify M. tb adaptations to this host environment as well as M. tb mechanisms/factors contributing to increased active and disseminated TB during M. tb/HIV co-infection.
2014-03-31 | GSE49760 | GEO