Project description:The mammalian gastrointestinal tract and the bloodstream are highly disparate biological niches, and yet certain commensal-pathogenic microorganisms are able to thrive in both environments. Here, we report the evolution of a unique transcription circuit in the yeast, Candida albicans, which determines its fitness in both host niches. Our comprehensive analysis of the DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved transcriptional repressors, Sfu1 and Hap43. The Sef1 activator of iron uptake genes promotes virulence in a mouse model of bloodstream infection, whereas the Sfu1 repressor is dispensable for virulence but promotes gastrointestinal commensalism. We propose that the ability to alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut may be a fundamental attribute of gastrointestinal commensal-pathogens.
Project description:The mammalian gastrointestinal tract and the bloodstream are highly disparate biological niches, and yet certain commensal-pathogenic microorganisms are able to thrive in both environments. Here, we report the evolution of a unique transcription circuit in the yeast, Candida albicans, which determines its fitness in both host niches. Our comprehensive analysis of the DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved transcriptional repressors, Sfu1 and Hap43. The Sef1 activator of iron uptake genes promotes virulence in a mouse model of bloodstream infection, whereas the Sfu1 repressor is dispensable for virulence but promotes gastrointestinal commensalism. We propose that the ability to alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut may be a fundamental attribute of gastrointestinal commensal-pathogens.
Project description:The mammalian gastrointestinal tract and the bloodstream are highly disparate biological niches, and yet certain commensal-pathogenic microorganisms are able to thrive in both environments. Here, we report the evolution of a unique transcription circuit in the yeast, Candida albicans, which determines its fitness in both host niches. Our comprehensive analysis of the DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved transcriptional repressors, Sfu1 and Hap43. The Sef1 activator of iron uptake genes promotes virulence in a mouse model of bloodstream infection, whereas the Sfu1 repressor is dispensable for virulence but promotes gastrointestinal commensalism. We propose that the ability to alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut may be a fundamental attribute of gastrointestinal commensal-pathogens. ChIP analyses to profile genome-wide of distribution of Sef1, Sfu1 and Hap43 in response to various iron availability. 12 independent ChIP experiments were performed on 6 biological replicates of the untagged control and 2 biological replicates each of Sef1-Myc, Sfu1-Myc, and Hap43-Myc.
Project description:Interventions: Group 1: Arm 1: Blood-, urine- and stool-samples of 60 patients with gastrointestinal tumors (UICC III-IV) without tumor cachexia will be frozen. The samples will be collected and send to the analysis lab for analysis. In addition, a questionnaire will be completed by the patient.
Group 2: Arm 2: Blood-, urine- and stool-samples of 60 patients with gastrointestinal tumors (UICC III-IV) with tumor cachexia will be frozen. The samples will be collected and send to the analysis lab for analysis. In addition, a questionnaire will be completed by the patient.
Primary outcome(s): - Evaluation of intestinal genes in stool samples of patients using next-generation sequencing technology
- Identification of differences regarding the diversity of intestinal microorganisms between both groups
Primary and endpoint will be assessed once based on the collected samples. No follow-up samples will be collected.
Study Design: Allocation: ; Masking: ; Control: ; Assignment: ; Study design purpose: basic science
Project description:Keratinocytes are the major constituent of epithelial cells at mucosal surfaces and skin, which cover organs, internal cavities and the body. Traditionally, keratinocytes have been considered as an inert component of the multilayered epithelium to protect the subepithelial compartments from the pathogenic microorganisms, toxic stimuli and physical trauma. However, accumulated researches of the airway, gastrointestinal tract and skin have demonstrated that keratinocytes function in the development of the immune system, promotion of pathologic inflammation and even impose diverse decisions on immune cells. We used microarrays to detail the global gene expression of oral keratinocyte during oral adaptive immune response.
Project description:Keratinocytes are the major constituent of epithelial cells at mucosal surfaces and skin, which cover organs, internal cavities and the body. Traditionally, keratinocytes have been considered as an inert component of the multilayered epithelium to protect the subepithelial compartments from the pathogenic microorganisms, toxic stimuli and physical trauma. However, accumulated researches of the airway, gastrointestinal tract and skin have demonstrated that keratinocytes function in the development of the immune system, promotion of pathologic inflammation and even impose diverse decisions on immune cells. We used microarrays to detail the global gene expression of oral keratinocyte during oral adaptive immune response. Oral keratinocyte were collected at three time points (control, 48h and 96h) in oral adaptive immune response for RNA extraction and hybridization on Affymetrix microarrays
Project description:Persons with Chronic Granulomatous Disease, are susceptible to a narrow range of infections resulting from the failure of cells to generate toxic reactive oxygen species (ROS) required for phagocytice oxidative killing of microorganisms. For unknown reasons, many inflammatory conditions (inflammatory bowel disease, periodontal inflammation, granulomatous obstruction of the urinary and gastrointestinal tract and “sterile” inflammation of the lungs and other organs) are also associated with the disease. The goal of this study is to investigate the role of ROS in the regulation of inflammatory and immunity genes induced by Toll-like Receptors (TLRs). Transcriptional responses to peptidoglycan or lipopolysaccharide (TLR2/4 agonists) were evaluated at 4 and 24 hrs in peripheral blood monocytes (PBM) from three males with CGD compared to PBM from 5 healthy individuals.