Human Macrophage Gamma Interferon Decreases Gene Expression but Not Replication of<i>Mycobacterium tuberculosis</i>: Analysis of the Host-Pathogen Reciprocal Influence on Transcription in a Comparison of Strains H37Rv and CMT97

Cappelli, Giulia; Volpe, Pietro; Sanduzzi, Alessandro; Sacchi, Alessandra; Colizzi, Vittorio; Mariani, Francesca

doi:10.1128/iai.69.12.7262-7270.2001

Cited by 29 publications

(27 citation statements)

References 39 publications

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“…Fractionation studies and immunoblot analyses performed on culture-grown M. tuberculosis found that the Eis protein was distributed throughout the bacterium, including the cell wall and cytoplasm (7). More recent studies have shown that eis is differentially expressed in a clinical strain of M. tuberculosis upon infection of activated human macrophages (4). These results do not suggest a function for the Eis protein or indicate how eis may be regulated.…”

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confidence: 49%

Molecular Characterization of the eis Promoter of Mycobacterium tuberculosis

et al. 2004

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To further understand. Experiments were done to characterize the eis promoter in M. smegmatis and M. tuberculosis H37Ra. The putative ؊10 and ؊35 regions matched the Escherichia coli 70 consensus 67 and 83%, respectively, making it a group A/SigA-like mycobacterial promoter. Expression of site-directed variants of the core promoter region, determined by flow cytometry using gfp as a reporter, showed that the putative ؊10 region is essential for eis expression. In addition, site-directed alteration of the eis promoter to the consensus E. coli 70 promoter elements increased gfp transcription to levels similar to that driven by the heat shock promoter, phsp60, of Mycobacterium bovis BCG. Upstream promoter deletion analysis showed that a 200-and 412-bp region of the promoter was necessary for maximum expression of gfp in M. smegmatis and M. tuberculosis H37Ra, respectively. Random mutagenesis of the 412-bp eis promoter, using a catechol 2,3-dioxygenase screen and activity assay, defined nucleotides upstream of the core promoter region that are essential to eis expression in both M. smegmatis and M. tuberculosis H37Ra, including a region homologous to a DinR cis element.Tuberculosis (TB) continues to be the world's most destructive human bacterial infectious disease. Current estimates show that more than two million people die from TB each year, and TB remains a major cause of premature death (18). Mortality due to TB is a major global health crisis due to AIDS and the increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis, although effective treatments are available. Despite the elucidation of the genome sequence of several M. tuberculosis strains (5, 14) and available genetic tools to identify genes involved in TB pathogenesis (13,16,23,26), the molecular basis of its ability to survive within host cells and evade host immune responses is unknown. Understanding the molecular mechanisms of pathogenesis is essential for the development of better methods of diagnosis, treatment, and prevention. One way to heighten our understanding of M. tuberculosis pathogenesis is to examine the regulation of potential virulence genes, in particular the promoters and other elements that govern their expression.Approximately 130 mycobacterial promoters have been characterized to date, but only 76 have been categorized into the four groups (A to D) of mycobacterial promoters (15). Identified promoters comprise less than 3% of the potential promoters in the genome of M. tuberculosis. The majority of the categorized promoters are from Mycobacterium smegmatis and Mycobacterium paratuberculosis, with less than 25% derived from M. tuberculosis itself. This indicates that we know little about promoter function in mycobacteria and even less about promoters from M. tuberculosis. Therefore, there is a need for detailed studies on M. tuberculosis promoter characterization and function, especially for genes that may play a role in the survival of M. tuberculosis within macrophages.The eis gene of M. tuberculosis H37Rv...

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confidence: 49%

Molecular Characterization of the eis Promoter of Mycobacterium tuberculosis

et al. 2004

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“…[34][35][36] Studies on gene expression profiles of Mtbinfected human macrophages provided the evidence for the importance of IL-1b and IL-12 in combating Mtb. 37 Importantly, one study identified CCL1, produced from macrophages of TB patients after Mtb stimulation, was involved in host susceptibility to TB. 38 Here, we demonstrated that miR-20a-5p was reduced after mycobacterial infection in vitro and in vivo, which implicates this pathway maybe a potential defense mechanism to promote an effective immune response against infection.…”

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Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

et al. 2016

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Induction of cell apoptosis is one of the major host defense mechanisms through which macrophages control Mycobacterium tuberculosis (Mtb) infection. However, the mechanisms underlying macrophage apoptosis triggered by Mtb infection are still largely unknown. In this study, a microarray profiling survey revealed 14 miRNAs were down-regulated in CD14C monocytes from active pulmonary tuberculosis patients, and only the reduction of miR-20a-5p could be reversed after successful anti-tuberculosis treatment. Validation of miR-20a-5p expression was confirmed using real time qPCR. Moreover, miR-20a-5p expression also decreased in differentiated THP-1 macrophages after mycobacterial infection in vitro. Functional assays through forced or inhibited expression of miR-20a-5p in THP-1 macrophages demonstrated that miR-20a-5p functioned as a negative regulator of mycobacterial-triggered apoptosis. Importantly, inhibition of miR-20a-5p expression resulted in more efficient mycobacterial clearance from infected THP-1 macrophages while miR-20a-5p overexpression promoted mycobacterial survival. Mechanistically, miR-20a-5p was demonstrated to regulate Bim expression in a JNK2-dependent manner, unlike Bcl2, and luciferase assay showed JNK2 was a novel direct target of miR-20a-5p. Together, our findings indicate that downregulation of miR-20a-5p triggers macrophage apoptosis as a novel mechanism for host defense against mycobacterial infection.

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“…Eis is involved in the survival of mycobacteria during the infection of macrophages (16). It has been shown that Eis is expressed only when the clinical isolate was replicating in activated macrophages (24). However, nothing is known about how Eis mediates its functional activity.…”

Section: Discussionmentioning

confidence: 99%

Eis (Enhanced Intracellular Survival) Protein of Mycobacterium tuberculosis Disturbs the Cross Regulation of T-cells

Lella

Sharma

2007

Journal of Biological Chemistry

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The pathogenesis of tuberculosis is complex and its manifestations diverse, reflecting a lifetime of dynamic interactions between mycobacterial virulence factors and the human immune system. The pathogenic mycobacteria have developed strategies to circumvent the major killing mechanisms employed by macrophages and take advantage of the enclosed environment within its host cell to avoid humoral and cell-mediated immune responses. Secretory proteins play a major role in host-pathogen interactions. The eis (Rv2416c) gene has been identified as a secretory protein, and it has been shown that it enhances intracellular survival of Mycobacterium semgmatis in the macrophage cell line. The main aim of this study was to gain insight into the biological role of Eis in the host. Stimulation of T-cells with Eis recombinant protein of Mycobacterium tuberculosis inhibits Con A-mediated T-cell proliferation in vitro.

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Human Macrophage Gamma Interferon Decreases Gene Expression but Not Replication ofMycobacterium tuberculosis: Analysis of the Host-Pathogen Reciprocal Influence on Transcription in a Comparison of Strains H37Rv and CMT97

Cited by 29 publications

References 39 publications

Molecular Characterization of the eis Promoter of Mycobacterium tuberculosis

Molecular Characterization of the eis Promoter of Mycobacterium tuberculosis

Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

Eis (Enhanced Intracellular Survival) Protein of Mycobacterium tuberculosis Disturbs the Cross Regulation of T-cells

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