Type I IFN-signaling following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE18607 | GEO | 2010/07/07
SECONDARY ACCESSION(S): PRJNA121433
REPOSITORIES: GEO
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Project description:Type I IFN-signaling suppresses an excessive IFN-{gamma} response and prevents lung damage and chronic inflammation following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice. Type I IFN -signaling in pulmonary CD11c+ DCs and alveolar macrophages may prevent chronic inflammation following PC lung infection and clearance by suppressing an excessive IFN-g-response via the induction of SOCS1. IFNAR-/- and wildtype mice were both Pneumocystis infected via itratracheal instillation. Pulmonary CD11c+ cells were isolated from collagen digested lungs at day 7 and day 14 post infection from both wildtype and IFNAR-/- mice using a magnetic cell sorting technique from Miltenyi with CD11c microbeads. Cells from three individual animals per group were isolated and assessed. Comparison of 2 treatment types at 2 timepoints to determine whether type I IFN signaling is initiated in resident and early recruited pulmonary CD11c+ cells following Pneumocystis lung infection and whether this is relevant to the outcome of the inflammatory response during the initiation of clearance.
2010-07-07 | E-GEOD-18607 | biostudies-arrayexpress
Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of +2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.
2012-01-18 | E-GEOD-23508 | biostudies-arrayexpress
Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison
2012-01-18 | GSE23508 | GEO
Project description:In wild-type mice, expression of chemokines that are ligands for Ccr2, Cxcr3, and Cxcr2 increased at days 32 to 41 post-infection, with a return to baseline by day 75. Concomitant increases were seen in Ccr2 and Cxcr3 but not in Cxcr2 expression. Induction of these same factors also occurred in CD40-ligand and CD40 knockout mice but only at a much later time-point, during uncontrolled Pneumocystis pneumonia (PCP). Expression of CD4 Th1 markers was increased in wild-type mice during clearance of infection. Ccr2 and Cx3cr1 knockout mice cleared Pneumocystis infection with kinetics similar to wild-type mice, and all animals developed anti-Pneumocystis antibodies. Upregulation of Ccr2 and Cxcr3 and their ligands supports an important role for T helper cells and mononuclear phagocytes in the clearance of Pneumocystis infection. However, based on the current and prior studies, no single chemokine receptor appears to be critical to the clearance of Pneumocystis.
2015-10-10 | GSE67720 | GEO
Project description:In wild-type mice, expression of chemokines that are ligands for Ccr2, Cxcr3, and Cxcr2 increased at days 32 to 41 post-infection, with a return to baseline by day 75. Concomitant increases were seen in Ccr2 and Cxcr3 but not in Cxcr2 expression. Induction of these same factors also occurred in CD40-ligand and CD40 knockout mice but only at a much later time-point, during uncontrolled Pneumocystis pneumonia (PCP). Expression of CD4 Th1 markers was increased in wild-type mice during clearance of infection. Ccr2 and Cx3cr1 knockout mice cleared Pneumocystis infection with kinetics similar to wild-type mice, and all animals developed anti-Pneumocystis antibodies. Upregulation of Ccr2 and Cxcr3 and their ligands supports an important role for T helper cells and mononuclear phagocytes in the clearance of Pneumocystis infection. However, based on the current and prior studies, no single chemokine receptor appears to be critical to the clearance of Pneumocystis.
2015-10-10 | GSE67718 | GEO
Project description:β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study we examined whether β-1,3 glucans are masked by surface proteins in Pneumocystis, and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including P. jirovecii, which causes Pneumocystis pneumonia (PCP) in humans, P. carinii, and P. murina, β-1,3 glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using Q-PCR and microarray techniques, we demonstrated in a mouse model of PCP that treatment with caspofungin, an inhibitor of β-1,3 glucan synthesis, for 21 days, decreased expression of a broad panel of inflammatory markers, including IFN-γ, TNF-α, IL-1β, IL-6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.
2016-08-31 | GSE79079 | GEO
Project description:Pulmonary hypertension (PH) is a disease of diverse etiology. While primary PH can develop in the absence of prior disease, PH more commonly develops in conjunction with other pulmonary pathologies. We previously reported a mouse model in which PH occurs as a sequelae of Pneumocystis infection in the context of transient CD4 depletion. Here, we demonstrate that instead of the expected Th2 pathways, the Th1 cytokine IFN-M-NM-3 was essential for the development of PH, as wild type mice developed PH, but not IFN-M-NM-3 knockout mice. Because gene expression analysis showed few strain differences that were not immune function related, we focused on those responses as potential pathologic mechanisms. While there were several differences in cellular and cytokine response that warrant further examination, we focused on three important aspects. First, if CD4 cells were continuously depleted, but the infection was limited by antibiotic treatment, then PH did not occur, confirming that CD4 T-cells are required for PH development. Second, although CD8 T-cells are implicated in the pathology of unabated Pneumocystis pneumonia, they did not have a role in the onset of PH. Finally, although there are differences in the amounts of the pulmonary immune cells, differences existed in phenotypes of immune cells that correlated with PH, such as elevated CD204 expression in lung CD11c+ cells. Two groups of BALB/c mice (3 per group) were infected i.t. with 10e7 Pneumocystis; one of those groups also received 4 injections of CD4 T-cell depleting antibodies beginning 3 days prior to infection and ending 7 days after infection. A third group was IFN-gamma knockout mice infected with Pneumocystis and depleted of CD4 cells in the same way. A fourth group of control non-treated BALB/c mice were also used. AT 38 days post infection, lung tissues were taken, and RNA was extracted to allow for differential gene expression analysis
2013-10-27 | E-GEOD-51750 | biostudies-arrayexpress
Project description:Pneumocystis murina and Pneumocystis carinii RNA-Seq transcriptome
| PRJNA292577 | ENA
Project description:HIV-infected persons are at increased risk for developing pulmonary diseases including chronic obstructive pulmonary disease (COPD), and the fungal opportunistic pathogen, Pneumocystis jirovecii (Pc) has been implicated in the pathogenesis of HIV-related COPD. We previously developed a non-human primate model of HIV-related COPD using simian-human immunodeficiency virus (SHIV) and Pc co-infection in cynomolgus macaques. In the present study we examined gene expression profiles in lung tissue from SHIV/Pc co-infected monkeys with COPD and compared them to SHIV-infected monkeys infected with normal lung function. Microarray technology was used to develop gene profiles, and differential gene expression was determined by a comparative evaluation of competing normalization methods applied to our expression data set followed by validation using quantitative real-time polymerase chain reaction analysis for select genes. Of over 52,000 transcripts representing more than 20,000 genes analyzed, the SHIV/Pc infected macaques with COPD exhibited 243 differentially expressed (DE) genes compared to SHIV-infected monkeys with normal lung function. DE genes fell into a number of functional categories which may be important in COPD development including: inflammation (pulmonary surfactants A2, B, C, D, upregulated; alternative macrophage activation-associated CC chemokine, upregulated), protease/antiprotease balance (cathepsin H, upregulated; alpha-1-chymotrypsin and secretory leukocyte peptidase inhibitor, downregulated), redox balance (glutathione peroxidase 4 and mitochondrial aldehyde dehydrogenase 2, upregulated) and tissue homeostasis (connective tissue growth factor, downregulated; ornithine decarboxylase antizyme, upregulated). These results identify factors and pathways that may be involved in early development of Pneumocystis and SHIV-associated COPD and reveal several novel, potential therapeutic targets. There are totally 11 samples in the experiment. The sample breakdown is as follows: KN14(group 1) is a true control in that the monkey was not infected with simian-human immunodeficiency virus (SHIV) nor was it colonized with Pneumocystis. KN02, KN03, KN07 and KN08 (group 2) are also controls of a sort. They were infected with SHIV but they did not become colonized with Pneumocystis. The remainder (KN01, KN04, KN06, KN11, KN12, KN13) (group3) were both infected with SHIV and colonized with Pneumocystis. The primary interest is in comparing the two SHIV-infected groups (2 and 3)
2010-09-25 | E-GEOD-24343 | biostudies-arrayexpress
Project description:With the extensive use of glucocorticoids (GCs), the occurrence of immunocompromised patients is increasingly raised. Pneumonia, caused by opportunistic pathogens including Pneumocystis (PC), is a major cause of morbidity and mortality. The loss of adaptive immune responses have been demonstrated as a key reason for the infection of Pneumocystis. Nevertheless, the alterations of innate immunity by GCs treatment and the subsequent effects remain unclear. Here we integrated the single-cell RNA sequencing and metabolomic analysis to decipher the alterations of the innate immunity in immunocompromised mice with PC infection. Our results have shown that a group of Mmp12+ macrophages was enriched in lung tissues of the immunocompetent mice upon PC infection. Pathway enrichment analysis showed obviously up-regulated pro-inflammatory pathways, suggesting that these Mmp12+ macrophages may be essential for the protection against PC infection. In the dexamethasone (DEX)-treated mice, the monocyte differentiation towards Mmp12+ macrophages was dramatically hampered via downregulating the granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Further, DEX treatment simultaneously impaired the metabolic and functional integrity of resident macrophages through down-regulating lysophosphatidylcholine and GM-CSF. These induced suppressed host antimicrobial capacities. The results of our study provides a rich resource for understanding the heterogeneity and changes in macrophages and also provides novel insights into immune response take place in GCs-induced immunosuppressed mice during PC infection.
2023-06-05 | GSE225246 | GEO