Adjunctive therapy with a phosphodiesterase-4 inhibitor improves INH response to pulmonary tuberculosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Oryctolagus cuniculus
PROVIDER: GSE74687 | GEO | 2015/12/21
SECONDARY ACCESSION(S): PRJNA301210
REPOSITORIES: GEO
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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: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:Tuberculosis kills nearly 2 million people through out the world, every year. The outcome of M. tuberculosis infection is determined by the host and bacterial factors. A strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including chemotaxis and proliferation of effector cells. The infecting bacilli counteracts the bactericidal activities of the host immune cells, primarily by modifying their gene expression. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. Tumor necrosis factor-alpha (TNF-a), produced by the immune cells, is an important cytokine in protecting the host against Mtb infection. However, excessive TNF-a production leads to severe inflammation and host cell destruction. In fact, pharmacologic inhibition of TNF-a production has been considered as a therapeutic modality in inflammatory diseases. Interestingly, inhibitors of host phosphodiesterase-4 (PDE4) have been shown to reduce TNF-a production and dampen inflammation without complete immune suppression of the host. In this study, we have explored the use of one of the PDE4 inhibitors, CC-3052, as an adjunct immune modulatory drug, in combination with isoniazid (INH) treatment in rabbit pulmonary tuberculosis. We hypothesize that reducing TNF-a levels during Mtb infection would reduce the environmental pressure on the bacteria, rendering them more amenable to killing by INH. Mtb infected rabbits were treated with CC-3052 or INH or both and the lung tissue were harvested after 4 and 8 weeks of treatment. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared between various treatment groups. The results of our study provides data to support the idea that combining anti-TB drugs with an adjunctive immune modulator may enhance the efficacy of current TB therapy regimens and shorten the duration of treatment if applied appropriately to humans. The microarray experiments involves 2 comparison groups. 1) Changes in rabbit gene expression between Mtb infected and uninfected animals; 2). Changes in rabbit gene expression between CC-3052 treated and untreated animals during Mtb infection at 4,8 and 12 weeks post infection. New Zealand White rabbits were infected with Mtb HN878 at 3.2log10 (on day 0). At 4 weeks post infection, one group of infected rabbits were treated with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, and the treatment was continued up to 12 weeks post infection. The compound was used at 25mg/kg body weight, dissolved in distilled water and administered through gavage five days a weeks. Lung tissue from Uninfected, Mtb-infected and Untreated or CC-3052 treated rabbits were isolated at Day0, 4,8 and 12 weeks post infection and used for total RNA extraction. Only the 8 and 12 week timepoints correspond to the associated publication.
2011-03-16 | E-GEOD-27992 | biostudies-arrayexpress
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs.
2013-08-17 | GSE49947 | GEO
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs. New Zealand White rabbits were infected with Mtb HN878 or CDC1551 at ~3.5log10. At 3 hours post infection, lung tissue from Mtb-infected and uninfected rabbits were isolated and used for total RNA extraction. Total rabbit lung RNA was used for microarray analysis to determine infection induced changes in host gene expression.
2013-08-17 | E-GEOD-49947 | biostudies-arrayexpress
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.
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Project description:Tuberculosis kills nearly 2 million people through out the world, every year. The outcome of M. tuberculosis infection is determined by the host and bacterial factors. A strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including chemotaxis and proliferation of effector cells. The infecting bacilli counteracts the bactericidal activities of the host immune cells, primarily by modifying their gene expression. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. Tumor necrosis factor-alpha (TNF-a), produced by the immune cells, is an important cytokine in protecting the host against Mtb infection. However, excessive TNF-a production leads to severe inflammation and host cell destruction. In fact, pharmacologic inhibition of TNF-a production has been considered as a therapeutic modality in inflammatory diseases. Interestingly, inhibitors of host phosphodiesterase-4 (PDE4) have been shown to reduce TNF-a production and dampen inflammation without complete immune suppression of the host. In this study, we have explored the use of one of the PDE4 inhibitors, CC-3052, as an adjunct immune modulatory drug, in combination with isoniazid (INH) treatment in rabbit pulmonary tuberculosis. We hypothesize that reducing TNF-a levels during Mtb infection would reduce the environmental pressure on the bacteria, rendering them more amenable to killing by INH. Mtb infected rabbits were treated with CC-3052 or INH or both and the lung tissue were harvested after 4 and 8 weeks of treatment. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared between various treatment groups. The results of our study provides data to support the idea that combining anti-TB drugs with an adjunctive immune modulator may enhance the efficacy of current TB therapy regimens and shorten the duration of treatment if applied appropriately to humans. The microarray experiments involves 2 comparison groups. 1) Changes in rabbit gene expression between Mtb infected and uninfected animals; 2). Changes in rabbit gene expression between CC-3052 treated and untreated animals during Mtb infection at 4,8 and 12 weeks post infection.
2011-03-16 | GSE27992 | GEO
Project description:Every year, tuberculosis kills nearly 1.8 million people through out the world. Though outcome of M. tuberculosis infection into active disease is determined by the host and bacterial factors, a strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts active disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including activation, maturation, chemotaxis and proliferation of effector cells. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. In this study, we have analysed the systematic changes in the global host gene expression profile in the lungs of Mtb infected rabbits at various stages of infection. Mtb infected rabbit lung tissues were isolated at T=0,2, 4 and 16 weeks post-infection. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared . Our data suggests a strong correlation between the significant changes in the global transcriptome of infected rabbits and the progression of Mtb infection into a chronic, cavitary TB disease. The microarray experiments involves comparison of: 1) Changes in rabbit gene expression between Mtb-HN878 infected and uninfected animals at 2,4 and 16 weeks post infection. New Zealand White rabbits were infected with Mtb HN878 at 3.2log10 (on day 0). Lung tissue from Mtb-infected rabbits were isolated at Day0, 2, 4 and 16 weeks post infection and used for total RNA extraction.
2011-12-07 | E-GEOD-33094 | biostudies-arrayexpress
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.
2012-07-11 | GSE39219 | GEO
Project description:Every year, tuberculosis kills nearly 1.8 million people through out the world. Though outcome of M. tuberculosis infection into active disease is determined by the host and bacterial factors, a strong host immune response controls the growth of the bacilli effectively. However, in a host with suboptimal immune response, the bacilli grows and mounts active disease. Activation of immune response following M. tuberculosis infection affects the expression of many host genes that are involved in the production of immune system molecules such as cytokines, chemokines, surface receptors and transcriptional regulators that manifest in the change of subsequent cellular events, including activation, maturation, chemotaxis and proliferation of effector cells. However, the specific nature of the host-pathogen interactions and the outcome of Mtb infection are not fully understood. In this study, we have analysed the systematic changes in the global host gene expression profile in the lungs of Mtb infected rabbits at various stages of infection. Mtb infected rabbit lung tissues were isolated at T=0,2, 4 and 16 weeks post-infection. Lung bacterial load, histologic changes and host and bacterial gene expression were determined for each timepoint and compared . Our data suggests a strong correlation between the significant changes in the global transcriptome of infected rabbits and the progression of Mtb infection into a chronic, cavitary TB disease. The microarray experiments involves comparison of: 1) Changes in rabbit gene expression between Mtb-HN878 infected and uninfected animals at 2,4 and 16 weeks post infection.
2011-12-07 | GSE33094 | GEO