Immunology Group

Delhi, India

Immunology Group

Delhi, India
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Jamwal S.,Immunology Group | Jamwal S.,Jaipur National University | Midha M.K.,Immunology Group | Midha M.K.,Jaipur National University | And 4 more authors.
Scientific Reports | Year: 2013

To probe how the pathogen Mycobacterium tuberculosis controls host cellular death pathways, we compared mitochondrial responses in human macrophages infected either with the avirulent mycobacterial strain H37Ra, or its virulent counterpart H37Rv. Following H37Ra infection, induction of the apoptotic response was foreshadowed by the early suppression of stress-induced mitochondrial activity. In contrast, mitochondria in H37Rv-infected cells displayed robust activity with increased membrane potential and ATP synthesis. An examination of the mitochondrial proteome revealed that attenuation of mitochondrial function was also coupled with the vigorous activation of bactericidal mechanisms in H37Ra-infected cells. In contrast, augmentation of mitochondrial activity by H37Rv enabled manipulation of host cellular mechanisms to inhibit apoptosis on the one hand, while ensuring fortification against anti-microbial pathways on the other. These results thus provide novel insights into the molecular interplay that facilitates adaptation of virulent mycobacteria within the hostile intracellular milieu of the host macrophage.


Pal D.,Visva Bharati University | Dasgupta S.,Visva Bharati University | Dasgupta S.,CSIR - Central Electrochemical Research Institute | Kundu R.,Visva Bharati University | And 7 more authors.
Nature Medicine | Year: 2012

Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100g-Gly123 and Thr493g-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes. © 2012 Nature America, Inc. All rights reserved.


Singh V.,Immunology Group | Jamwal S.,Immunology Group | Jain R.,Immunology Group | Verma P.,National Institute of Immunology | And 3 more authors.
Cell Host and Microbe | Year: 2012

Upon infection, Mycobacterium tuberculosis (Mtb) metabolically alters the macrophage to create a niche that is ideally suited to its persistent lifestyle. Infected macrophages acquire a "foamy" phenotype characterized by the accumulation of lipid bodies (LBs), which serve as both a source of nutrients and a secure niche for the bacterium. While the functional significance of the foamy phenotype is appreciated, the biochemical pathways mediating this process are understudied. We found that Mtb induces the foamy phenotype via targeted manipulation of host cellular metabolism to divert the glycolytic pathway toward ketone body synthesis. This dysregulation enabled feedback activation of the anti-lipolytic G protein-coupled receptor GPR109A, leading to perturbations in lipid homeostasis and consequent accumulation of LBs in the macrophage. ESAT-6, a secreted Mtb virulence factor, mediates the enforcement of this feedback loop. Finally, we demonstrate that pharmacological targeting of pathways mediating this host-pathogen metabolic crosstalk provides a potential strategy for developing tuberculosis chemotherapy. © 2012 Elsevier Inc.


Shafiani S.,Seattle Biomedical Research Institute | Dinh C.,Seattle Biomedical Research Institute | Ertelt J.,Cincinnati Childrens Hospital Medical Center | Moguche A.,Seattle Biomedical Research Institute | And 11 more authors.
Immunity | Year: 2013

Thymically derived Foxp3+ regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity. © 2013 Elsevier Inc..


Raghuvanshi S.,Immunology Group | Sharma P.,Immunology Group | Singh S.,All India Institute of Medical Sciences | Van Kaer L.,Vanderbilt University | Das G.,Immunology Group
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Tuberculosis (TB) is the cause of 2 million deaths each year, which is the second highest cause of mortality from a single infectious disease worldwide. Resistance of these organisms to drugs has emerged as an important health concern. Alternative approaches to the prevention and treatment of tuberculosis are therefore urgently needed. Despite the generation of robust host immune responses, Mycobacterium tuberculosis (M. tb) successfully evades host immunity and establishes a persistent infection. The mechanism( s) by which M. tuberculosis manages to persist in the face of potent host immune responses remain(s) incompletely understood Here, we demonstrate that M. tb suppresses T-lymphocyte responses by recruiting mesenchymal stem cells (MSCs) to the site of infection. We found that MSCs infiltrated tissues in mice containing M. tb organisms and T lymphocytes. We further demonstrate that MSCs suppressed T-cell responses by producing nitric oxide. Our findings reveal a key role of MSCs in the capacity of M. tb to evade host immune responses and identify these cells as unique targets for therapeutic intervention in tuberculosis.


Chatterjee S.,Immunology Group | Dwivedi V.P.,Immunology Group | Singh Y.,Immunology Group | Singh Y.,Royal Veterinary College University of London | And 5 more authors.
PLoS Pathogens | Year: 2011

Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2-/-) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy. © 2011 Chatterjee et al.


Kumar D.,Immunology Group | Nath L.,Immunology Group | Kamal Md.A.,Immunology Group | Varshney A.,Immunology Group | And 3 more authors.
Cell | Year: 2010

We performed a genome-wide siRNA screen to identify host factors that regulated pathogen load in human macrophages infected with a virulent strain of Mycobacterium tuberculosis. Iterative rounds of confirmation, followed by validation, identified 275 such molecules that were all found to functionally associate with each other through a dense network of interactions. This network then yielded to a molecular description of the host cell functional modules that were both engaged and perturbed by the pathogen. Importantly, a subscreen against a panel of field isolates revealed that the molecular composition of the host interface varied with both genotype and the phenotypic properties of the pathogen. An analysis of these differences, however, permitted identification of those host factors that were invariantly involved, regardless of the diversification in adaptive mechanisms employed by the pathogen. Interestingly, these factors were found to predominantly function through the regulation of autophagy. © 2010 Elsevier Inc. All rights reserved.


Mehrotra P.,Immunology Group | Jamwal S.V.,Immunology Group | Saquib N.,Immunology Group | Sinha N.,Immunology Group | And 4 more authors.
PLoS Pathogens | Year: 2014

The success of Mycobacterium tuberculosis as a pathogen derives from its facile adaptation to the intracellular milieu of human macrophages. To explore this process, we asked whether adaptation also required interference with the metabolic machinery of the host cell. Temporal profiling of the metabolic flux, in cells infected with differently virulent mycobacterial strains, confirmed that this was indeed the case. Subsequent analysis identified the core subset of host reactions that were targeted. It also elucidated that the goal of regulation was to integrate pathways facilitating macrophage survival, with those promoting mycobacterial sustenance. Intriguingly, this synthesis then provided an axis where both host- and pathogen-derived factors converged to define determinants of pathogenicity. Consequently, whereas the requirement for macrophage survival sensitized TB susceptibility to the glycemic status of the individual, mediation by pathogen ensured that the virulence properties of the infecting strain also contributed towards the resulting pathology. © 2014 Mehrotra et al.


Chatterjee S.,Immunology Group | Kumar D.,Immunology Group
PLoS ONE | Year: 2011

Cellular signaling networks display complex architecture. Defining the design principle of this architecture is crucial for our understanding of various biological processes. Using a mathematical model for three-node feed-forward loops, we identify that the organization of motifs in specific manner within the network serves as an important regulator of signal processing. Further, incorporating a systemic stochastic perturbation to the model we could propose a possible design principle, for higher-order organization of motifs into larger networks in order to achieve specific biological output. The design principle was then verified in a large, complex human cancer signaling network. Further analysis permitted us to classify signaling nodes of the network into robust and vulnerable nodes as a result of higher order motif organization. We show that distribution of these nodes within the network at strategic locations then provides for the range of features displayed by the signaling network. © 2011 Chatterjee, Kumar.


Sethi S.,Justus Liebig University | Nanda R.,Immunology Group | Chakraborty T.,Justus Liebig University
Clinical Microbiology Reviews | Year: 2013

This review article introduces the significance of testing of volatile organic compounds (VOCs) in clinical samples and summarizes important features of some of the technologies. Compared to other human diseases such as cancer, studies on VOC analysis in cases of infectious diseases are limited. Here, we have described results of studies which have used some of the appropriate technologies to evaluate VOC biomarkers and biomarker profiles associated with infections. The publications reviewed include important infections of the respiratory tract, gastrointestinal tract, urinary tract, and nasal cavity. The results highlight the use of VOC biomarker profiles resulting from certain infectious diseases in discriminating between infected and healthy subjects. Infection- related VOC profiles measured in exhaled breath as well as from headspaces of feces or urine samples are a source of information with respect to disease detection. The volatiles emitted in clinical matrices may on the one hand represent metabolites of the infecting pathogen or on the other hand reflect pathogen-induced host responses or, indeed, a combination of both. Because exhaled- breath samples are easy to collect and online instruments are commercially available, VOC analysis in exhaled breath appears to be a promising tool for noninvasive detection and monitoring of infectious diseases. © 2013, American Society for Microbiology. All Rights Reserved.

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