<i>Mycobacterium tuberculosis</i>infection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells

Danelishvili, Lia; McGarvey, Jeffery A.; Li, Yongjun; Bermudez, Luiz E.

doi:10.1046/j.1462-5822.2003.00312.x

Cited by 188 publications

(188 citation statements)

References 58 publications

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“…U937 human monocytic cell line (ATCC CRL-1593-2) and human monocyte derived macrophages were cultured as reported in ref. 33. Human monocytes were obtained from the blood of volunteers, using protocols approved by the Institutional Human Subject committee.…”

Section: Methodsmentioning

confidence: 99%

Identification ofMycobacterium aviumpathogenicity island important for macrophage and amoeba infection

Danelishvili

Stang

et al. 2007

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

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The ability to infect macrophages is a common characteristic shared among many mycobacterial species. Mycobacterium avium, Mycobacterium tuberculosis, and Mycobacterium kansasii enter macrophages, using the complement receptors CR1, CR3, CR4, and the mannose receptor. To identify M. avium genes and host cell pathways involved in the bacterial uptake by macrophages, we screened a M. avium transposon mutant library for the inability to enter macrophages. Uptake-impaired clones were selected. Sequence of six M. avium clones identified one gene involved in glycopeptidolipid biosynthesis, one gene encoding the conserved membrane protein homologue to the M. avium subsp. paratuberculosis MAP2446c gene and four others belonging to the same region of the chromosome. Analysis of the chromosome region revealed a pathogenicity island inserted between two tRNA sequences with 58% of G؉C content versus 69% in the M. avium genome. The region is unique for M. avium and is not present in M. tuberculosis or M. paratuberculosis. Although the mutants did not differ from the WT bacterium regarding the binding to macrophage cell membrane, analysis of macrophage proteins after 1 h infection revealed a deficiency in the mutant to phosphorylate certain proteins on uptake. To understand M. avium interaction with two evolutionarily distinct hosts, the mutants were evaluated for Acanthamoeba castellanii invasion. The defect in the ability of the mutants to invade both cells was highly similar, suggesting that M. avium might have evolved mechanisms that are used to enter amoebas and human macrophages. uptake M ycobacterium avium complex is an intracellular pathogen that can infect a variety of host cells (1-4). M. avium, like the majority of pathogenic mycobacteria, infects and replicates within macrophages (5, 6), which are the phagocytic cells where M. avium establishes a long-term infection (7).A number of studies in vitro have determined that M. avium, in a manner similar to Mycobacterium tuberculosis, is taken up by macrophages using the complement receptors CR3, CR4, and CR1 (8-10), and/or the mannose receptor (8, 11). M. tuberculosis has been found to bind to the CD11b chain of the ␤-integrin of the CR3 and CR4 receptors, which happened without participation of the serum complement proteins (10). Other studies demonstrated that the mannose capped lipoarabinomannan antigen of virulent M. tuberculosis cell wall is capable to recognize and bind to the mannose receptors on the macrophage membrane (11).It has been hypothesized that virulent mycobacteria bind to many receptors because pathogenic mycobacteria would use several different receptors on the macrophage membrane to be internalized, as a strategy to guarantee phagocytosis, even when a sitespecific macrophage would not contain one or more membrane receptors. In addition, this property would address the possibility that mycobacteria may not express all of the ligands during all phases of infection. Most mycobacteria evolved to survive inside phagocytic cells, although they can enter ...

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Section: Methodsmentioning

confidence: 99%

Identification ofMycobacterium aviumpathogenicity island important for macrophage and amoeba infection

Danelishvili

Stang

et al. 2007

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

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“…55 In addition, alveolar epithelial cell lines in culture are subject to necrosis by virulent but not attenuated mycobacterial organisms. 56,57 The attenuation of BCG is related to the loss of the RD1 locus encoding ESAT-6, which is responsible in part for the cytolysis of pneumocytes by virulent mycobacteria. 58 The ability of GM-CSF to prevent epithelial cytotoxicity by virulent mycobacteria early in the course of the infection, underlies the significantly reduced rate of mortality of GMOE mice.…”

Section: Discussionmentioning

confidence: 99%

Granulocyte–macrophage colony stimulating factor-mediated innate responses in tuberculosis

et al. 2008

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“…4 Pathogen escapes killing mechanisms of toxic reactive oxygen or nitrogen intermediates by limiting phagocytic cells to generate these most effective anti-bacterial molecules. 5,6 Mtb contains molecular strategies to hijack trafficking pathways to prevent autophagy and the destruction of macrophages by apoptosis [7][8][9] that has been proposed to be the virulence characteristic of Mtb. Many manners, employed by Mtb, have been described to inhibit a macrophage self-death, [7][8][9][10][11] leading to the conclusion that this property must be an important one for the pathogen survival outcome.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] Alveolar epithelial cells are also subjected to the same destiny when infected with Mtb. 7,14 Evidence suggests that upon infection of macrophages, Mtb induces an anti-apoptotic mechanism by suppressing TNF-a-mediated extrinsic apoptosis but, concomitantly, pathogen activates the intrinsic pathway through mitochondrial damage, 11 which leads to necrosis as an exit strategy. 11,15 Experimental models have shown that the RD1 region, present in both M. tuberculosis and Mycobacterium marinum, is involved in the necrosis process and deficiency to secrete ESAT-6 and CFP-10 proteins results in impairment of both pathogen to exit macrophages.…”

Section: Introductionmentioning

confidence: 99%

“…Our laboratory has demonstrated that Mtb partially inhibits macrophage apoptosis. 7 The evidence shows that the inhibition of the extrinsic pathway is post-transcriptional, and the intrinsic pathway of apoptosis is used to trigger the cell death. 11,20 The association of intrinsic pathway of apoptosis and necrosis has been recently documented.…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosisPPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages

2015

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Alveolar macrophages are the main line of innate immune response against M. tuberculosis (Mtb) infection. However, these cells serve as the major intracellular niche for Mtb enhancing its survival, replication and, later on, cell-to-cell spread. Mtb-associated cytotoxicity of macrophages has been well documented, but limited information exists about mechanisms by which the pathogen induces cell necrosis. To identify virulence factors involved in the induction of necrosis, we screened 5,000 transposon mutants of Mtb for clones that failed to promote the host cell necrosis in a similar manner as the wild-type bacterium. Five Mtb mutants were identified as potential candidates inducing significantly lower levels of THP-1 cell damage in contrast to the H37Rv wild-type infection. Reduced levels of the cell damage by necrosis deficient mutants (NDMs) were also associated with delayed damage of mitochondrial membrane permeability when compared with the wild-type infection over time. Two knockout mutants of the Rv3873 gene, encoding a cell wall PPE68 protein of RD1 region, were identified out of 5 NDMs. Further investigation lead to the observation that PPE68 protein interacts and exports several unknown or known surface/secreted proteins, among them Rv2626c is associated with the host cell necrosis. When the Rv2626c gene is deleted from the genome of Mtb, the bacterium displays significantly less necrosis in THP-1 cells and, conversely, the overexpression of Rv2626c promotes the host cell necrosis at early time points of infections in contrast to the wild-type strain.

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Mycobacterium tuberculosisinfection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells

Cited by 188 publications

References 58 publications

Identification ofMycobacterium aviumpathogenicity island important for macrophage and amoeba infection

Identification ofMycobacterium aviumpathogenicity island important for macrophage and amoeba infection

Granulocyte–macrophage colony stimulating factor-mediated innate responses in tuberculosis

Mycobacterium tuberculosisPPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages

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