Rifampicin drug resistant Mycobacterium tuberculosis infection suppresses in vivo immune responses through a Type I Interferon response.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE176423 | GEO | 2022/06/01
REPOSITORIES: GEO
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Project description:The emergence of multidrug resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, resistant to the frontline anti-tubercular drugs rifampicin and isoniazid, forces treatment with less effective and toxic second-line drugs and stands to derail TB control efforts. However, the immune response to MDR Mtb infection remains poorly understood. Here, we determined the RNA transcriptional profile of in vitro generated macrophages to infection with either drug susceptible Mtb HN878 or MDR Mtb W_7642 infection.
2018-12-26 | GSE115495 | 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:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis
2015-03-31 | E-GEOD-67427 | 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: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: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.
2013-06-28 | GSE48027 | 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.
2012-07-11 | GSE39219 | 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: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
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