References of "Tallam, Aravind 50003169"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailGene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages
Antony, Paul UL; Tallam, Aravind UL; Perumal, Thanneer Malai UL et al

in PLoS ONE (2016)

Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein ... [more ▼]

Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. To this end, we studied IRG1 expression in human immune cells under different inflammatory stimuli, such as TNFα and IFNγ, in addition to lipopolysaccharides. Under these conditions, as previously shown in mouse macrophages, IRG1/CAD accumulates in mitochondria. Furthermore, using literature information and transcription factor prediction models, we re-constructed raw gene regulatory networks (GRNs) for IRG1 in mouse and human macrophages. We further implemented a contextualization algorithm that relies on genome-wide gene expression data to infer putative cell type-specific gene regulatory interactions in mouse and human macrophages, which allowed us to predict potential transcriptional regulators of IRG1. Among the computationally identified regulators, siRNA-mediated gene silencing of interferon regulatory factor 1 (IRF1) in macrophages significantly decreased the expression of IRG1/CAD at the gene and protein level, which correlated with a reduced production of itaconic acid. Using a synergistic approach of both computational and experimental methods, we here shed more light on the transcriptional machinery of IRG1 expression and could pave the way to therapeutic approaches targeting itaconic acid levels. [less ▲]

Detailed reference viewed: 204 (14 UL)
See detailReconstruction of IRG1 Gene Regulatory Network in Mammalian Macrophages under Inflammatory Conditions
Tallam, Aravind UL

Doctoral thesis (2015)

The immune system is the first line of defence against invading pathogens. Macrophages are the key effector cells of the innate immune system which produce an array of cytokines, antimicrobial peptides ... [more ▼]

The immune system is the first line of defence against invading pathogens. Macrophages are the key effector cells of the innate immune system which produce an array of cytokines, antimicrobial peptides, and effector molecules pathogen in response to pathogen invasion. Immunoresponsive gene 1 (Irg1) is highly upregulated when mouse macrophages are stimulated with LPS. Recently, the function of Irg1 has been elucidated as a gene coding for a protein which catalyses the decarboxylation of cis-aconitate, a tricarboxylic acid (TCA) cycle intermediate, to itaconic acid. In turn, itaconic acid selectively inhibits isocitrate lyase, a key enzyme of the glyoxylate shunt, which is a saviour pathway for bacteria to grow on low carbon diets. Thus, Irg1 via the production of itaconic acid plays an important role in combating pathogen invasion. Despite the importance of this recent discovery, the upstream transcriptional machinery of IRG1 has not yet been investigated. Hence, the aim of this thesis was to elucidate the gene regulatory networks of IRG1 in mammalian macrophages under inflammatory conditions. To achieve this aim, the experimental protocols for the isolation of monocytes from peripheral blood and their differentiation into macrophages were implemented. The cells were then characterised based on their morphology and the expression profile of cellular marker genes to confirm their identity. Using this cellular model, I discovered IRG1 expression and itaconic acid production in human macrophages under LPS activation. Both IRG1 and itaconic acid were initially discovered elsewhere in murine macrophages upon LPS stimulation. I further analysed the dynamics of IRG1 expression and itaconic acid production using different bacterial and viral ligands in human and mouse macrophages, showing that IRG1 expression could be upregulated when mammalian cells encounter bacteria and viruses. Owing to the complex upstream transcriptional machinery for IRG1 expression, I implemented a workflow defined as transcription factor identification protocol (TFIP) using both experimental and computational methods to identify potential transcription regulators for IRG1 expression in human and mouse macrophages. siRNA mediated gene silencing experiments in human and mouse macrophages revealed IRF1 as a transcriptional regulator for IRG1 in both the species and CEBPB in mouse macrophages under LPS activation. [less ▲]

Detailed reference viewed: 164 (43 UL)
Full Text
Peer Reviewed
See detailEnhancement of COPD biological networks using a web-based collaboration interface
Boue, Stephanie; Fields, Brett; Hoeng, Julia et al

in F1000Research (2015), 4(32), 1-22

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD ... [more ▼]

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website (https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be used to help understand the mechanisms related to lung pathobiology. Registered users of the website can freely browse and download the networks. [less ▲]

Detailed reference viewed: 59 (2 UL)
Full Text
Peer Reviewed
See detailImmune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, Alessandro UL; Cordes, Thekla UL; Ghelfi, Jenny UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an ... [more ▼]

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. [less ▲]

Detailed reference viewed: 445 (131 UL)