Elucidating Host-Pathogen Interaction in Acute Systemic Candidiasis in a Mouse Model Using Genomic Approach
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE16339 | GEO | 2010/12/31
SECONDARY ACCESSION(S): PRJNA115271
REPOSITORIES: GEO
Similar Datasets
Project description:Candida species is a common fungus that had evolved as both commensal and opportunistic pathogen in humans. The rise in human morbidity and mortality caused by Candida species sparked an alarming concern. However, the thin line between commensalism and infection as well as the analysis of Candida host-pathogen interactions has not been completely elucidated prior to the birth of global gene expression technologies. Gene expression analysis of host response upon systemic candidiasis had been carried out using Beadarray and validated by using GenomeLab™ GeXP multiplex PCR. Whole blood from infected mouse was isolated, globin mRNA depleted through subtractive hybridization and its RNA purified. Results from microarray data demonstrated increased expression of genes involved in the pathogen recognition, signal transduction, inflammation, microbial killing and in antigen processing. Interestingly, we also discovered possible increment of erythropoiesis in our animal model and this lead us to believe that Candida tropicalis might possess potent haemolytic factors to sequester iron from the host erythrocytes. Taken together, our data also suggest novel genes such as syndecans and dendritic cell immunoreceptor which might be exploited by Candida tropicalis in its pathogenesis in the host. Nevertheless, the challenge ahead is to understand the specific roles of these genes that underlies in Candida tropicalis pathogenesis. For gene expression analysis, BALB/c mice (six-week-old female weighing 20-25g) were used and the animals were randomized, assigned to the control, sublethal infection and lethal infection groups. At the time of killing, mice were anesthetized and exsanguinated by cardiac puncture. Approximately 200 µl of whole blood was collected and added into 2 ml tubes preloaded with RNAlater (Sigma-Aldrich CO, USA) and stored in -80 °C.
2010-12-31 | E-GEOD-16339 | biostudies-arrayexpress
Project description:Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species-specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the species differences in terms of virulence, ecological niches, and prevalence among these three species.
2017-01-30 | GSE81514 | GEO
Project description:The opportunistic fungal pathogen Candida albicans is a common cause of life-threatening nosocomial bloodstream infections. In the murine model of systemic candidiasis the kidney is the primary target organ while the fungal load declines over time in liver and spleen. To get a better understanding of the organ-specific differences in host-pathogen interaction during systemic murine candidiasis, we performed a time-course gene expression profiling to investigate the differential responses of murine kidney, liver and spleen and determined the fungal transcriptome in liver and kidney. We clearly demonstrate a delayed immune response on the transcriptional level in kidney accompanied by late induction of fungal stress response genes in this organ. In contrast, early upregulation of the proinflammatory response in the liver was associated with a fungal transcriptional profile resembling that of phagocytosed cells, suggesting that the resident phagocytic system contributes significantly to fungal control in the liver. Although no visible filamentation occurred in the liver, C. albicans hypha-associated genes were upregulated, indicating an uncoupling of gene expression and morphology during infection of this organ. In vitro the induction of hypha-associated gene expression in yeast cells led to altered interaction with macrophages, suggesting that the observed transcriptional changes affect host-pathogen interaction in vivo. Consistently, the combination of host and pathogen transcriptional data in an inference network model implied that C. albicans cell wall remodeling and metabolism were connected to the immune responses in kidney and liver. Furthermore, the network suggested links between fungal iron acquisition and amino acid metabolism in the kidney and host organ homeostasis. Thus, this work provides novel insights into the organ-specific host-pathogen interactions during systemic C. albicans infection.
2016-11-18 | GSE83679 | GEO
Project description:The opportunistic fungal pathogen Candida albicans is a common cause of life-threatening nosocomial bloodstream infections. In the murine model of systemic candidiasis the kidney is the primary target organ while the fungal load declines over time in liver and spleen. To get a better understanding of the organ-specific differences in host-pathogen interaction during systemic murine candidiasis, we performed a time-course gene expression profiling to investigate the differential responses of murine kidney, liver and spleen and determined the fungal transcriptome in liver and kidney. We clearly demonstrate a delayed immune response on the transcriptional level in kidney accompanied by late induction of fungal stress response genes in this organ. In contrast, early upregulation of the proinflammatory response in the liver was associated with a fungal transcriptional profile resembling that of phagocytosed cells, suggesting that the resident phagocytic system contributes significantly to fungal control in the liver. Although no visible filamentation occurred in the liver, C. albicans hypha-associated genes were upregulated, indicating an uncoupling of gene expression and morphology during infection of this organ. In vitro the induction of hypha-associated gene expression in yeast cells led to altered interaction with macrophages, suggesting that the observed transcriptional changes affect host-pathogen interaction in vivo. Consistently, the combination of host and pathogen transcriptional data in an inference network model implied that C. albicans cell wall remodeling and metabolism were connected to the immune responses in kidney and liver. Furthermore, the network suggested links between fungal iron acquisition and amino acid metabolism in the kidney and host organ homeostasis. Thus, this work provides novel insights into the organ-specific host-pathogen interactions during systemic C. albicans infection.
2016-11-18 | GSE83681 | GEO
Project description:The opportunistic fungal pathogen Candida albicans is a common cause of life-threatening nosocomial bloodstream infections. In the murine model of systemic candidiasis the kidney is the primary target organ while the fungal load declines over time in liver and spleen. To get a better understanding of the organ-specific differences in host-pathogen interaction during systemic murine candidiasis, we performed a time-course gene expression profiling to investigate the differential responses of murine kidney, liver and spleen and determined the fungal transcriptome in liver and kidney. We clearly demonstrate a delayed immune response on the transcriptional level in kidney accompanied by late induction of fungal stress response genes in this organ. In contrast, early upregulation of the proinflammatory response in the liver was associated with a fungal transcriptional profile resembling that of phagocytosed cells, suggesting that the resident phagocytic system contributes significantly to fungal control in the liver. Although no visible filamentation occurred in the liver, C. albicans hypha-associated genes were upregulated, indicating an uncoupling of gene expression and morphology during infection of this organ. In vitro the induction of hypha-associated gene expression in yeast cells led to altered interaction with macrophages, suggesting that the observed transcriptional changes affect host-pathogen interaction in vivo. Consistently, the combination of host and pathogen transcriptional data in an inference network model implied that C. albicans cell wall remodeling and metabolism were connected to the immune responses in kidney and liver. Furthermore, the network suggested links between fungal iron acquisition and amino acid metabolism in the kidney and host organ homeostasis. Thus, this work provides novel insights into the organ-specific host-pathogen interactions during systemic C. albicans infection.
2016-11-18 | GSE83680 | GEO
Project description:Candida tropicalis is an opportunistic pathogen which causes candidiasis in immune-compromised individuals. It is one of the members of the non-albicans group of Candida that are known to be azole resistant and is frequently seen in individuals being treated for cancers, HIV-infection and bone-marrow transplant. Although the genome of C. tropicalis was sequenced in the year 2009, the genome annotation has not been supported by experimental validation. In the present study, we have carried out in-depth proteomic profiling of C. tropicalis using high-resolution Fourier transform mass spectrometry and mapped ~44% of the computationally predicted protein-coding genes with peptide level evidence. In addition to identifying 2,740 proteins in the cell lysate of this yeast, we also analysed the proteome of the conditioned media of C. tropicalis culture and identified several unique secreted proteins among a total of 780 proteins. By subjecting the mass spectrometry data derived from cell lysate and conditioned media to proteogenomic analysis, we identified 86 novel genes, 12 novel exons and corrected 49 computationally predicted gene models. To our knowledge, this is the first high-throughput proteomic study to refine the genome annotation of C. tropicalis.
2017-05-08 | PXD001071 | Pride
Project description:Candidiasis affects a wide variety of immunocompromised individuals, including HIV/AIDS patients and cancer patients on chemotherapy. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, that are genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo. Unexpectedly, both strains showed a dramatic reduction in organ fungal burden and clearance of infection in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling did not reveal any significant changes in the host immune response to UME6 expression in the NACS. Interestingly, however, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly down-regulated. Our findings are significant because they suggest fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicans.
2019-10-01 | GSE134321 | GEO
Project description:Homo sapiens fresh whole blood was infected with Candida tropicalis. RNA-pool of both species extracted at 0min (control), 15, 30, 60, 120, 240 min. Samples are rRNA depleted. Measurement of Candida tropicalis gene expression.
2019-07-31 | GSE114178 | GEO
Project description:The yeast-filament transition is essential for the virulence of a variety of fungi that are pathogenic to humans. N-acetylglucosamine (GlcNAc), a ubiquitous molecule in both the environment and host, is one of the most potent inducers of filamentation in Candida albicans and thermally dimorphic fungi such as Histoplasma capsulatum and Blastomyces dermatitidis. However, GlcNAc suppresses rather than promotes filamentation in Candida tropicalis, a fungal species that is closely related to C. albicans. Furthermore, we discover that glucose induces filamentous growth in C. tropicalis. Mutation and overexpression assays demonstrate that the conserved cAMP signaling pathway plays a central role in the regulation of filamentation in C. tropicalis. Activation of this pathway promotes filamentation in C. tropicalis, while inactivation of this pathway results in a serious growth defect in filamentation. By screening an overexpression library of 154 transcription factors, we have identified approximately 40 regulators of filamentous growth in C. tropicalis. Although most of the regulators (e.g., Tec1, Gat2, Nrg1, Sfl1, Sfl2, and Ash1) demonstrate a conserved role in the regulation of filamentation, similar to their homologs in C. albicans or S. cerevisiae, some of them are specific to C. tropicalis. For example, Czf1 and Efh1 repress filamentation, while Wor1, Zcf3, and Hcm1 promote filamentation in C. tropicalis. Bcr1, Aaf1, and Csr1 play a specific role in the process of GlcNAc-regulated filamentation. Our findings indicate that multiple interconnected signaling pathways are involved in the regulation of filamentation in C. tropicalis. These mechanisms have conserved and divergent features among different Candida species.
2016-07-01 | GSE73340 | GEO
Project description:Among ~5,000,000 fungal species on Earth, Candida albicans is exceptional in its lifelong association with humans, where it exists either as a benign component of the gastrointestinal microbiome or as an invasive pathogen. Although it is generally assumed that invasiveness results from a breakdown of host immunity , it is also possible that specific fungal programs control the transition between these divergent lifestyles. Here, we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 has been thought to occur only in unique genetic backgrounds, but we show that WOR1 expression is triggered when wild-type cells are propagated in a murine gastrointestinal infection model. Similar to Wor1’s role in a white-opaque switch for mating, WOR1 overexpression within the host induces a novel switch affecting cell and colony morphology and conferring commensal fitness. However, these hyperfit GUT (Gastrointestinally-IndUced Transition) cells lack the functional hallmarks of opaque cells, which they resemble morphologically, whereas bona fide opaque cells are defective for commensalism. Instead, the GUT cell transcriptome is optimized for the environment of the distal mammalian digestive tract. The GUT cell type switch illuminates how a single organism can utilize distinct genetic programs to transition between commensalism and invasive tissue pathogenesis Candida albicans strains including the Wild type strain (SN425), WOR1OE -White (a/a, SN1044), WOR1OE -GUT (a/a, SN1045), White (a/a, SN966) and Opaque (a/a, SN967) were grown at room temperature in SC medium supplemented with 100ug/ml adenine; 2-4 biological replicates were performed per strain. RNA was prepared from these strains and samples were hybridized on custom Agilent C. albicans ORF arrays (15,000 spots/array, 70-mer probes).
2013-07-28 | E-GEOD-43972 | biostudies-arrayexpress