The effect of Mtb aggregation on monocyte-derived macrophage transcription profiles
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173560 | GEO | 2021/04/30
REPOSITORIES: GEO
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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. 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) secretes several virulence determinants that alter phagosome biogenesis, enabling its survival within the cell. Nevertheless, the mechanism underlying this process remains considerably obscure. Here, we have identified a novel regulatory mechanism whereby SIRT7 mediates Rac1 activation in cytoskeletal remodelling during Mtb infection. We found that SIRT7 are significantly decreased during Mtb infection in both mRNA and protein levels. SIRT7 deficiency impairs macrophage phagocytosis and bacteriacidal activity by disrupts actin cytoskeleton dynamics. In the murine TB model, the deficiency of Sirt7 had an adverse effect on the host's response to Mtb since it led to an increase in bacterial burden and inflammation in the lung. Conversely, the overexpression of Sirt7 impeded bacterial growth. Mechanistically, we have shown that SIRT7 limits Mtb infection by directly interacting with and activating RAC1. Therefore, we conclude that SIRT7 is responsible for driving cytoskeletal remodeling through RAC1, thus providing crucial insight into host response during Mtb infection and offering a potential target for tuberculosis treatment.
2023-12-20 | GSE245205 | 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.
2011-03-16 | GSE27992 | GEO
Project description:We have found that drug-resistant (DR) Mtb infection alters the host pathogen interactions thought to occur during drug-sensitive (DS) Mtb infection. Recent data suggests that lack of both, Type I and IL-1, signaling pathways leads to susceptibility to infection to DR Mtb infection. To understand the pathways involved in maintaining control of DR Mtb infection, we are sequencing the bulk lung cells early in infection.
2024-04-03 | GSE249400 | GEO
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:We have found that drug-resistant (DR) Mtb infection alters the host pathogen interactions thought to occur during drug-sensitive (DS) Mtb infection. Recent data suggests that lack of IL-1, but not Type I IFN, signaling pathways leads to susceptibility to infection to DR Mtb infection. To understand the pathways involved in maintaining control of DS Mtb infection, we are sequencing the bulk lung cells early in infection.
2024-04-03 | GSE249401 | GEO
Project description:The lung is a key site of Mtb infection. We profiled the lung ecosystem of mice following Mtb infection.
2023-06-03 | GSE229190 | GEO
Project description:The macrophage is a cellular reservoir for Mtb infection. We profiled BMDM following Mtb infection.
2023-06-01 | GSE232320 | GEO
Project description:To compare gene expression changes induced by infection with Mycobacterium tuberculosis (Mtb) with changes induced by purified Mtb products, we infected THP-1 cells with Mtb strain H37Rv or treated with purified Mtb products, then performed RNAseq.
2023-05-15 | GSE227851 | 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