Mycobacterium tuberculosis bearing pulmonary transcriptomic landscape of wildtype and PD-1 deficient mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE261737 | GEO | 2024/09/01
REPOSITORIES: GEO
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Project description:The critical role of type I IFN (IFN I ) in viral disease is thoroughly documented while their function in bacterial infection remains ambiguous. General interest in biological functions of IFN I in Mycobacterium tuberculosis (Mtb) infection was raised by the identification of a distinct IFN I gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Increased survival was accompanied by reduced bacterial burden and ameliorated lung pathology as well as diminished production of proinflammatory IL-1?, among other cytokines. IFNAR1 signaling did not affect T cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung during pulmonary TB. This process was orchestrated by presence of IFNAR1 in both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by CXCL5/CXCL1-driven accumulation of neutrophils into alveoli and subsequently a distinct compartmentalization of Mtb in lung phagocytes. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to unleashed inflammation. Hence, our data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB. dual-color color-swap
2013-12-31 | E-GEOD-44848 | biostudies-arrayexpress
Project description:Tuberculosis (TB) is the leading cause of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (Mtb) infection is urgently needed. Complete and early Mtb control can be induced in M. bovis Bacillus Calmette–Guérin (BCG) vaccinated hosts when the innate immune response is targeted to generate effective vaccine-induced immunity. In the present study, we show that the superior and early Mtb control that is mediated by innate activation of DCs is associated with mucosal localization of clonal activated vaccine-induced CD4+ T cells in the lung. Our studies also show that the lung epithelial cell signaling through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB pathway is critical for the mucosal localization of activated vaccine-induced CD4+ T cells for rapid Mtb control. Thus, our study provides novel insights into the immune mechanisms that can overcome TB vaccine bottlenecks and provide early rapid Mtb control.
2021-09-14 | GSE150657 | GEO
Project description:Background: Mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis. Methods A novel cohort of patients with extra-pulmonary TB and sarcoidosis was recruited and the transcriptional response of these patients compared to those with pulmonary TB using a variety of transcriptomic approaches including testing a previously defined 380 gene meta-signature of active TB. Results The 380 meta-signature broadly differentiated active TB from healthy controls in this new dataset consisting of pulmonary and extra-pulmonary TB. The top 15 genes from this meta-signature had a lower sensitivity for differentiating extra-pulmonary TB from healthy controls as compared to pulmonary TB. We found the blood transcriptional responses in pulmonary and extra-pulmonary TB to be heterogeneous and to reflect the extent of symptoms of disease. Conclusions The transcriptional signature in extra-pulmonary TB demonstrated heterogeneity of gene expression reflective of symptom status, while the signature of pulmonary TB was distinct, based on a higher proportion of symptomatic individuals. These findings are of importance for the rational design and implementation of mRNA based TB diagnostics.
2016-11-04 | GSE83456 | GEO
Project description:Tuberculosis (TB) remains the leading cause of death by a single infectious agent worldwide. Despite decades of active research, host factors which underly susceptibility to Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, are still ill defined. We investigated the role of platelets (PLTs) during primary TB in mice as these cells were recently assigned multiple immunological functions. PLTs were present at the site of infection, formed aggregates with different myeloid subsets during experimental TB and such aggregates were detected also in TB patients. PLTs were detrimental during the early phase of infection and this effect was uncoupled from their canonical activation. PLTs left lung cell dynamics and patterns of anti-mycobacterial T-cell responses unchanged. PLTs hampered cell autonomous defense by restricting production of reactive oxygen species (ROS) in lung residing myeloid cells. Thus, PLTs orchestrate immunity in TB by modulating innate immune responsiveness during primary lung infection and may be amenable to new interventions for this deadly disease.
2020-12-22 | GSE137421 | GEO
Project description:The goal of this experiment was to examine the innate immune response to helminth infection in the lung. Hookworms (like many other helminths) use an obligate migration pathway through the lung. Their infection has been characterized in the gut in detail, but early immune responses in the lung have not been fully characterized. Experiment Overall Design: SCID mice were used to examine the innate immune response. SCID mice have no functional B or T cells but a fully functional innate immune system. SCID and WT mice were infected with 500 L3 stage infectious Nippostrongylus brasiliensis SC and their lungs were removed at days 2,3,4,8 and 12 post infection.
2007-12-01 | E-GEOD-3414 | biostudies-arrayexpress
Project description:The critical role of type I IFN (IFN I ) in viral disease is thoroughly documented while their function in bacterial infection remains ambiguous. General interest in biological functions of IFN I in Mycobacterium tuberculosis (Mtb) infection was raised by the identification of a distinct IFN I gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Increased survival was accompanied by reduced bacterial burden and ameliorated lung pathology as well as diminished production of proinflammatory IL-1?, among other cytokines. IFNAR1 signaling did not affect T cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung during pulmonary TB. This process was orchestrated by presence of IFNAR1 in both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by CXCL5/CXCL1-driven accumulation of neutrophils into alveoli and subsequently a distinct compartmentalization of Mtb in lung phagocytes. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to unleashed inflammation. Hence, our data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB.
2013-12-31 | GSE44848 | GEO
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: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.
2015-03-31 | GSE67427 | 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: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