Transcriptome analysis of pulmonary CCR2+ inflammatory monocytes challenged with Cryptococcus neoformans
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE122765 | GEO | 2019/02/11
REPOSITORIES: GEO
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Project description:Transcriptome analysis of pulmonary CCR2+ inflammatory monocytes challenged with Cryptococcus neoformans
| PRJNA506250 | ENA
Project description:Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes are the most abundant subset in the blood. They express a CD14+CD16-CCR2+ phenotype, which confers on them the ability to migrate to inflammatory sites by quickly responding to CCL2 signaling. Here we identified and characterized the surge and expansion of a novel monocyte subset during SIV and HIV infection. They were undistinguishable from classical monocytes regarding CD14 and CD16 expression, but did not express surface CCR2. Transcriptome analysis of sorted cells confirmed that they represent a distinct subpopulation that expresses lower levels of inflammatory cytokines and activation markers than their CCR2+ counterparts. They exhibited impaired phagocytosis and deficient chemotaxis in response to CCL2 and CCL7, besides being refractory to SIV infection. We named these cells atypical CCR2- classical (ACC) monocytes, and believe they play an important role in AIDS pathogenesis, possibly reflecting an anti-inflammatory response against the extreme immune activation observed during SIV and HIV infection. Antiretroviral therapy caused this population to decline in both macaque and human subjects, suggesting that this atypical phenotype may be induced by viral replication. Expression profiling by NanoString nCounter gene expression system. Classical monocytes (CD14++CD16-) from six SIV-infected macaques (day 14 post inoculation) were sorted in two groups according to CCR2 expression.
2012-03-01 | E-GEOD-27559 | biostudies-arrayexpress
Project description:Cryptococcus neoformans (Cn) is an opportunistic fungal microorganism that causes life-threatening meningoencephalitis. During the infection, the microbial population is heterogeneously composed of cells with varying generational ages, with older cells accumulating during chronic infections. This is attributed to their enhanced resistance to phagocytic killing and tolerance of antifungals like fluconazole (FLC). Using RNA-seq, we investigated how transcriptomic changes in different aspects of metabolism contribute to age-associated FLC tolerance in Cn.
2024-03-06 | GSE260902 | GEO
Project description:Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes are the most abundant subset in the blood. They express a CD14+CD16-CCR2+ phenotype, which confers on them the ability to migrate to inflammatory sites by quickly responding to CCL2 signaling. Here we identified and characterized the surge and expansion of a novel monocyte subset during SIV and HIV infection. They were undistinguishable from classical monocytes regarding CD14 and CD16 expression, but did not express surface CCR2. Transcriptome analysis of sorted cells confirmed that they represent a distinct subpopulation that expresses lower levels of inflammatory cytokines and activation markers than their CCR2+ counterparts. They exhibited impaired phagocytosis and deficient chemotaxis in response to CCL2 and CCL7, besides being refractory to SIV infection. We named these cells atypical CCR2- classical (ACC) monocytes, and believe they play an important role in AIDS pathogenesis, possibly reflecting an anti-inflammatory response against the extreme immune activation observed during SIV and HIV infection. Antiretroviral therapy caused this population to decline in both macaque and human subjects, suggesting that this atypical phenotype may be induced by viral replication. Expression profiling by NanoString nCounter gene expression system.
2012-03-01 | GSE27559 | GEO
Project description:Systemic infection with Cryptococcus neoformans, a dangerous and contagious pathogen found throughout the world, frequently results in lethal cryptococcal pneumonia and meningoencephalitis, and no effective treatments of cryptococcosis are available. Here, we describe Prm1, a novel regulator of virulence in C. neoformans. C. neoformans prm1 cells exhibit extreme sensitivity to various environmental stress conditions. Furthermore, prm1 cells show deficiencies in the biosynthesis of chitin, chitosan, and mannoprotein, which in turn result in impairment of cell wall integrity. Treatment of mice with heat-killed prm1 cells was found to facilitate the host immunological defence against infection with wild-type C. neoformans. Further investigation demonstrated that prm1 cells strongly promote pulmonary production of interferon- and Th1 responses, leading to activation of macrophage M1 differentiation and inhibition of M2 polarization. Therefore, our findings suggest that C. neoformans Prm1 may be a viable target for the development of anti-cryptococcosis medications and, cells lacking Prm1 represent a promising candidate for a vaccine.
2023-10-11 | PXD038840 | Pride
Project description:Cryptococcus neoformans is an invasive human fungal pathogen, which causes pneumonia and meningoencephalitis in both healthy and immunodeficient individuals, resulting 181,100 deaths each year. Studies have demonstrated that copper detoxification machineries play critical functions in modulating C. neoformans fitness and pathogenicity in the host lung tissue. Pulmonary C. neoformans infection provokes the generation of toxic copper bombardment, which in return activate detoxification process in fungal cells. However, the molecular mechanism on how Cu inhibits C. neoformans in proliferation remains unclear. Here, using Cu detoxification gene knockout strains we demonstrated that exogenous Cu ions inhibit cell growth of the metallothionein mutant, which was significantly rescue when supplementing with the ROS scavenger, N-acetylcysteine. To future characterize the molecular mechanism of C. neoformans response to Cu toxicity, we employ iTRAQ with LC-MS/MS analysis, in the presence of exogenous Cu or NAC. Our data showed that an increased Cu level repressed expression of factors involved in protein translation but activates expression of important players in ubiquitin-degradation process. We proposed that the downregulation of protein synthesis and the upregulation of protein degradation were the main strategy of Cu toxicity. The metallothionein mutant showed a higher ubiquitination level under Cu treatment. In addition, MG132 could partially restore the Cu toxicity effect on metallothionein mutant. These results shed new light on the Cu antifungal mechanisms from proteomic profile.
2021-02-09 | PXD024098 | iProX
Project description:Cryptococcus neoformans, an environmental opportunistic human fungal pathogen, is a causative agent for acute pulmonary infection and meningoencephalitis. Understanding the host’s response to C. neoformans infection is critical for developing effective treatment. Even though some have elucidated the host response at the transcriptome level, little is known about how it modulates its defense machinery through the proteome mechanism or how protein posttranslational modification responds to the infection. In this work, we employed a Cryptococcus murine infection model and mass spectrometry to systematically determine the proteome and acetylome statuses of two primary organs (lung and brain) in the early stage of infection. To extensively analyze the host response, we compared and integrated the proteome data to the transcriptome results. We demonstrated a significant overlap between two data sets. Critical genes, including genes involved in phagosome, lysosome, or osteoblast differentiation and platelet activation are significantly altered in protein and gene expression during infection. In the acetylome analysis, we demonstrated that lung and brain tissues differentially regulate protein acetylation during infection. The three primary groups of proteins altered in acetylation status are histones, proteins involved in glucose and fatty acid metabolism, and proteins from the immune system. These analyses provide an integrative regulation network of the host responding to C. neoformans and shed new light on understanding the host’s regulation mechanism when responding to C. neoformans.
2020-04-21 | PXD016614 | Pride
Project description:The kinase, putative endopeptidase and other peptides of small size (KEOPS) complex plays critical cellular functions in eukaryotes, but its pathobiological roles remains elusive in fungal pathogens. Here we comprehensively analyze the pathobiological functions of the KEOPS complex in fungal meningoencephalitis pathogen Cryptococcus neoformans. The cryptococcal KEOPS complex appears to have a linear arrangement of Pcc1-Kae1-Bud32-Cgi121, supported by physical interaction between Pcc1-Kae1, Kae1-Bud32, and Bud32-Cgi121, but does not have Gon7 ortholog, which is the part of the S. cerevisiae KEOPS complex. Deletion of PCC1, KAE1, and BUD32 causes severe growth defects with perturbed cell cycle control.
2022-10-18 | GSE208333 | GEO
Project description:Cryptococcus neoformans is an opportunistic basidiomycete pathogen that is a major etiological agent of fungal meningoencephalitis leading to more than 180,000 deaths worldwide annually. For this pathogen, the polysaccharide capsule is a key virulence factor, which interferes with the phagocytosis by host innate immune cells, but its complex signaling networks remain elusive. In this study, we systematically analyzed capsule biosynthesis and signaling networks by using C. neoformans transcription factor (TF) and kinase mutant libraries under diverse capsule-inducing conditions, such as Dulbecco’s Modified Eagle’s (DME), Littman’s medium (LIT) and fetal bovine serum (FBS) medium. We found that deletion of GAT201, YAP1, BZP4, and ADA2 consistently causes capsule production defects in all tested media, indicating that they are capsule-regulating core TFs. Epistatic and expression analysis showed that Yap1 and Ada2 control Gat201 upstream, whereas Bzp4 and Gat201 regulate capsule production independently. We next searched for potential upstream kinases and found that mutants deleted of PKA1, BUD32, POS5, IRE1 or CDC2801 showed reduced capsule production under all three capsule induction conditions, whereas mutants deleted of HOG1 and IRK5 displayed enhanced capsule production. Notably, Pka1 and Irk5 controls induction of GAT201 and BZP4, respectively, under capsule induction condition. Finally, we monitored transcriptome profiles governed by Bzp4, Gat201, and Ada2 under capsule-inducing condition and demonstrated that these TFs regulate redundant and unique sets of downstream target genes. In conclusion, this study provides further insight into the complex regulatory mechanism of capsule production related signaling pathways in C. neoformans.
2022-10-18 | GSE208163 | GEO
Project description:Leukocyte recruitment, a universal feature of tissue inflammation, is regulated by the interactions of chemokines with their G protein-coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CCL2, plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to enable unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition (DIA) mass spectrometry, both the proteome and phosphoproteome were quantified for FlpIn-HEK293T cells stably expressing CCR2, at six time points after activation with CCL2, in comparison with untreated cells. Differential expression analysis identified 699 significantly regulated phosphorylation sites located on 441 proteins. As expected, many of these proteins participate in canonical signal transduction pathways and the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In addition, we identified regulated phosphorylation sites in numerous proteins that exert functions in the nucleus, including several constituents of the nuclear pore complex. This study provides an unprecedented level of detail about CCR2 signalling and identifies potential novel targets for regulation of CCR2 function.
2020-04-08 | PXD015845 | Pride