Tuberculosis remains a major cause of death from an infectious disease worldwide, yet only 10% of people infected with Mycobacterium tuberculosis develop disease. Defining both necessary and sufficient immunologic determinants of protection remains a great scientific challenge. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify human potential candidate markers of host defense by studying gene expression profiles of macrophages, cells which, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene co-expression network analysis revealed an association between the cytokine, IL-32, and the vitamin D antimicrobial pathway in a network of IFN- and IL-15 induced defense response genes. IL-32 was sufficient for induction of the vitamin D-dependent antimicrobial peptides, cathelicidin and DEFB4, and generation of antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. The IL-15 induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent vs. active tuberculosis or healthy controls, and a co-expression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15 induced gene network. Inferring that maintaining M. tuberculosis in a latent state and preventing transition to active disease represents host resistance, we believe these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.
IL-32 is a molecular marker of a host defense network in human tuberculosis.
Specimen part, Subject
View SamplesThe process of parturition involves the complex interplay of factors that changes the excitability and contractile activity of the uterus. We have compared the relative gene expression profile of myometrium from rats before parturition (21 days pregnant) and during delivery using high-density DNA microarray. Of 8740 sequences available in the array a total of 3782 were detected as present. From the sequences that were significantly altered, 59 genes were upregulated and 82 genes were downregulated. We were able to detect changes in genes described to have altered expression level at term including connexin 43 and 26, cyclo-oxygenase 2 and oxytocin receptor as well as novel genes that have been not previously associated with parturition. Quantitative real time PCR on selected genes further confirmed the microarray data. Here we report for the first time that aquaporin5 (AQP5), a member of aquaporin (AQP) water channel family, was dramatically downregulated during parturition (~100 fold by microarray and ~50 fold by Real Time PCR). The emerging profile highlights biochemical cascades occurring in a period of about 36 hours that triggers parturition and the initiation of myometrium reverse remodeling after partum. The microarray analysis uncovered genes that were previously suspected to play a role in parturition. This regulation involves genes from immune/inflammatory response, steroid/lipids metabolism, calcium homeostasis, cell volume regulation, cell signaling, cell division, and tissue remodeling, suggesting the presence of multiple and redundant mechanisms altered in the process of birth.
No associated publication
No sample metadata fields
View SamplesThe immune mechanisms that control resistance vs. susceptibility to mycobacterial infection in humans were investigated by studying leprosy skin lesions, the site where the battle between the host and the pathogen is joined. Using an integrative genomics approach, we found an inverse correlation between of IFN-beta and IFN-gamma gene expression programs at the site of disease. The Type II IFN, IFN-gamma and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in the lesions from patients with the self-healing tuberculoid form of the disease and mediated antimicrobial activity against the pathogen, Mycobacterium leprae in vitro. In contrast, the Type I IFN, IFN-beta and its downstream genes, including IL-27 and IL-10, were induced in monocytes by M. leprae in vitro, and were preferentially expressed in the lesions of disseminated and progressive lepromatous form. The IFN-gamma induced macrophage antimicrobial response was inhibited by IFN-beta/IL-10, by a mechanism involving blocking the generation of bioactive 1,25-dihyroxy vitamin D as well as inhibiting induction of antimicrobial peptides cathelicidin and DEFB4. The ability of IFN-B to inhibit the IFN-gamma induced vitamin D pathway including antimicrobial activity was reversed by neutralization of IL-10, suggesting a possible target for therapeutic intervention. Finally, a common IFN-beta and IL-10 gene signature was identified in both the skin lesions of leprosy patients and in the peripheral blood of active tuberculosis patients. Together these data suggest that the ability of IFN-beta to downregulate protective IFN-gamma responses provides one general mechanism by which some bacterial pathogens of humans evade protective host responses and contribute to pathogenesis.
Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses.
Specimen part, Subject
View SamplesMicroarray analysis was performed on BWF1 mice spleenocyte cells in control and pCONS treated mice.
Distinct gene signature revealed in white blood cells, CD4(+) and CD8(+) T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide.
No sample metadata fields
View SamplesThis study examines the sites of HIV integration in quiescent CD4 T cells and compares them to activated T cells. The expression patterns of the sites hosting integration events were determined using microarray analysis data from quiescent and activated CD4 T cells.
Human immunodeficiency virus integration efficiency and site selection in quiescent CD4+ T cells.
No sample metadata fields
View SamplesLung tumors were induced in Kras LSL-G12D; Lkb1 fl/fl mice by intranasal inhalation of Adenoviral Cre. Four weeks after tumor induction, mice were randomly assigned into two groups and treated daily with either Vehicle or 1mg/kg MLN128 for 8 weeks. At the end of the study, mice were euthanized and tumors were dissected out from lung and snap frozen in liquid nitrogen. Frozen tumors were stored in -80C freezer. Lung squamous cell carcinomas adapted to chronic treatement with MLN128
No associated publication
Specimen part, Treatment
View SamplesOxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.
Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.
Cell line, Subject
View SamplesGene expression profiling was carried out on peripheral blood mononuclear cells from 45 adult females. The primary research question is whether leukocyte gene expression differs in individuals with varying levels of estrogen signaling.
No associated publication
No sample metadata fields
View SamplesGene expression profiling was carried out on peripheral blood mononuclear cell mRNA samples collected from renal cell carcinoma patients. The primary research question is whether gene expression differs as a function of patient's level of depression as measured by CESD score > 16.
Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: role of inflammatory signaling.
Specimen part, Disease
View SamplesGene expression profiling was carried out on peripheral blood CD2+ leukocytes from 29 children with asthma. The primary research question is whether gene expression differs in individuals from high socioeconomic status environments vs low socioeconomic status environments.
Genome-wide transcriptional profiling linked to social class in asthma.
No sample metadata fields
View Samples