Project description:Tuberculosis (TB) remains a deadly disease. The genetic diversity of Mycobacterium tuberculosis was neglected in the past, but is increasingly recognized as a determinant of immune responses and clinical outcomes of TB. However, how this bacterial diversity orchestrates immune responses to direct differences in TB severity remains unknown. We studied 681 patients with pulmonary TB and found that phylogenetically related M. tuberculosis isolates from cases with mild disease induced robust cytokine responses in macrophages. In contrast, isolates associated with severe TB cases failed to do so. Using representative isolates, we show that M. tuberculosis inducing a low cytokine response in macrophages also diminished activation of cytosolic surveillance systems, including cGAS and the inflammasome, suggesting a novel mechanism of immune escape. Isolates exhibiting this evasion strategy carried mutations in various components of the ESX-I secretion system. We conclude that host interactions with different M. tuberculosis strains results in variable TB severity.
Project description:Identification of genetic polymorphisms associated with inter-individual variation in immune response to Mycobacterium tuberculosis infection.
Project description:In this study we developed a guinea pig oligonucleotide microarray (GPOM) comprising of a total number of 45,220 features including 43,803 valid features from different mammalian species. These features are inclusive of 2971 newly annotated probes corresponding to 344 unique genes of guinea pig. As a case study, we utilized this array to examine the gene expression profile in guinea pig lungs in response to infection with Mycobacterium tuberculosis. Studying the global gene expression profile in guinea pigs allowed identification of the disease signature of pulmonary TB infection represented by several unique genes that are differentially regulated in this model. While, 1344 unique genes exhibited marked up regulation, 1856 genes were significantly down regulated. The newly developed tool not only finds its utility in studying the global gene expression profile associated with vaccination and/or M. tuberculosis infection in this highly useful animal model but would also be immensely useful in identification of new drug targets, testing of therapies, molecular genetic analysis for diseases other than tuberculosis as well.
Project description:In this study we developed a guinea pig oligonucleotide microarray (GPOM) comprising of a total number of 45,220 features including 43,803 valid features from different mammalian species. These features are inclusive of 2971 newly annotated probes corresponding to 344 unique genes of guinea pig. As a case study, we utilized this array to examine the gene expression profile in guinea pig lungs in response to infection with Mycobacterium tuberculosis. Studying the global gene expression profile in guinea pigs allowed identification of the disease signature of pulmonary TB infection represented by several unique genes that are differentially regulated in this model. While, 1344 unique genes exhibited marked up regulation, 1856 genes were significantly down regulated. The newly developed tool not only finds its utility in studying the global gene expression profile associated with vaccination and/or M. tuberculosis infection in this highly useful animal model but would also be immensely useful in identification of new drug targets, testing of therapies, molecular genetic analysis for diseases other than tuberculosis as well. Genotypic Technology designed Custom Cavia porcellus 4x44k Gene Expression Array (Agilent-AMADID-019424) * In order to validate the GPOM developed in this study, we compared the gene expression profile of guinea pig lungs at 10 weeks post- M. tuberculosis infection with respect to that obtained from normal uninfected animals. To address this, guinea pigs were aerosol infected with M. tuberculosis, lungs were harvested at 10 weeks post-infection and RNA obtained from infected lungs was employed for cDNA synthesis and microarray hybridization. The gene expression was compared with the RNA sample obtained from the lungs of normal uninfected guinea pigs.
Project description:Identification of genetic polymorphisms associated with inter-individual variation in immune response to Mycobacterium tuberculosis infection.
Project description:Identification of changes in microRNA expression, remodelling of relationships between microRNA and mRNA expression levels, and genetic polymorphisms associated with inter-individual variation in the dendritic cell immune response to Mycobacterium tuberculosis infection.
Project description:Identification of changes in microRNA expression, remodelling of relationships between microRNA and mRNA expression levels, and genetic polymorphisms associated with inter-individual variation in the dendritic cell immune response to Mycobacterium tuberculosis infection. We characterised genome-wide changes in microRNA expression, and of the broader miRNA-mdeiated regulatory system, in response to Mycobacterium tuberculosis (MTB) infection, and assessed the extent to which this response is under genetic control. To do so, we profiled microRNA expression levels in primary dendritic cells from 65 individuals before and after infection with MTB for 18 hours.
Project description:Pulmonary tuberculosis is a multigene disease, and some of the genes affect the development of Pulmonary tuberculosis. The study wants to find different expression genes in blood from Pulmonary tuberculosis patient and normal people who have genetic relationship wtih each other. We used microarrays to detail the global programme of gene expression in the blood between Pulmonary tuberculosis patient's and normal people's who have genetic relationship wtih each other.
Project description:The cytokine IL-10 deactivates macrophages and has been shown to impair resistance to mycobacterial infection. We have infected transgenic mice overexpressing IL-10 under control of the macrophage-specific CD68 promoter (macIL-10tg mice) with Mycobacterium tuberculosis by aerosol and found increased bacterial loads in the lungs of macIL-10tg mice. To identify programs of genes regulated by IL-10 and associated with increased mycobacterial replication, genome-wide expression analysis was performed. Experiment Overall Design: Impact of IL-10 pulmonary gene expression in mouse M. tuberculosis infection
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection.
