Protein Kinase G from Pathogenic Mycobacteria Promotes Survival Within Macrophages

Walburger, Anne; Koul, Anil; Ferrari, Giorgio; Nguyen, Liem; Prescianotto-Baschong, Cristina; Huygen, Kris; Klebl, Bert; Thompson, Charles J.; Bacher, Gerald; Pieters, Jean

doi:10.1126/science.1099384

Cited by 489 publications

(519 citation statements)

References 33 publications

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“…Several effector proteins from pathogenic bacteria were shown to mimick host proteins such as phosphatases or kinases to evade host immune defenses (33,35,(49)(50)(51). Because Mce3E has a DEF motif and could interact with ERK1/2 directly, we initially examined whether Mce3E could be able to dephosphorylate p-ERK directly, but we were not able to demonstrate the phosphatase activity of Mce3E toward p-ERK in vitro.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Chai

Zhang

et al. 2015

The Journal of Immunology

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Crucial to the pathogenesis of the tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis is its ability to subvert host immune defenses to promote its intracellular survival. The mammalian cell entry protein 3E (Mce3E), located in the region of difference 15 of the M. tuberculosis genome and absent in Mycobacterium bovis bacillus Calmette-Guérin, has an essential role in facilitating the internalization of mammalian cells by mycobacteria. However, relatively little is known about the role of Mce3E in modulation of host innate immune responses. In this study, we demonstrate that Mce3E inhibits the activation of the ERK1/2 signaling pathway, leading to the suppression of Tnf and Il6 expression, and the promotion of mycobacterial survival within macrophages. Mce3E interacts and colocalizes with ERK1/2 at the endoplasmic reticulum in a DEF motif (an ERK-docking motif)–dependent manner, relocates ERK1/2 from cytoplasm to the endoplasmic reticulum, and finally reduces the association of ERK1/2 with MEK1 and blocks the nuclear translocation of phospho-ERK1/2. A DEF motif mutant form of Mce3E (F294A) loses its ability to suppress Tnf and Il6 expression and to promote intracellular survival of mycobacteria. Inhibition of the ERK1/2 pathway in macrophages using U0126, a specific inhibitor of the ERK pathway, also leads to the suppressed Tnf and Il6 expression and the enhanced intracellular survival of mycobacteria. Taken together, these results suggest that M. tuberculosis Mce3E exploits the ERK1/2 signaling pathway to suppress host innate immune responses, providing a potential Mce3E–ERK1/2 interface–based drug target against M. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Chai

Zhang

et al. 2015

The Journal of Immunology

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“…R-Mtb is highly adapted to life within macrophages, and it can modulate macrophage defenses and inhibit the processing of its Ags for the MHC class II pathway to promote its intracellular survival (32,33). In particular, metabolically active M. tuberculosis is endowed with the capacity to arrest phagosomal maturation (34)(35)(36)(37). To find a possible explanation for the increased Ag presentation capacity of D-Mtb-infected macrophages, we tested whether D-Mtb shares with R-Mtb the same ability to arrest phagosomal maturation (38).…”

Section: Discussionmentioning

confidence: 99%

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Mariotti

Pardini

Gagliardi

et al. 2013

The Journal of Immunology

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Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative–specific human CD4+ T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB.

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“…Cells were again washed twice in PBS and incubated in DMEM͞FCS. Survival was determined at the indicated incubation times by bacterial incorporation of tritiated uracil followed by liquid scintillation counting (20). For antibiotic susceptibility testing, the infected monocytes were incubated in the presence of indicated spectinomycin concentrations for 48 h before permeabilization and mycobacterial labeling (see Supporting Text for details).…”

Section: Mycobacterial Survival In Monocytesmentioning

confidence: 99%

Ancestral antibiotic resistance in Mycobacterium tuberculosis

Morris

Nguyen

Gatfield

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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336

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Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection.Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibioticsensitive.multidrug resistance ͉ Streptomyces ͉ WhiB ͉ microarray ͉ gene expression

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Protein Kinase G from Pathogenic Mycobacteria Promotes Survival Within Macrophages

Cited by 489 publications

References 33 publications

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Ancestral antibiotic resistance in Mycobacterium tuberculosis

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