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      Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair

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          Abstract

          Induction of macrophage necrosis is an important strategy used by virulent Mycobacterium tuberculosis ( Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross priming by antigen presenting cells. Here we demonstrated that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions—a process crucial for preventing necrosis and promoting apoptosis—required the translocation of lysosome and Golgi apparatus-derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E 2 (PGE 2), which regulates synaptotagmin 7, the Ca ++ sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A 4 (LXA 4), which blocks PGE 2 biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.

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          A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).

          C J Vlahos, W Matter, K Hui … (1994)
          Phosphatidylinositol (PtdIns) 3-kinase is an enzyme implicated in growth factor signal transduction by associating with receptor and nonreceptor tyrosine kinases, including the platelet-derived growth factor receptor. Inhibitors of PtdIns 3-kinase could potentially give a better understanding of the function and regulatory mechanisms of the enzyme. Quercetin, a naturally occurring bioflavinoid, was previously shown to inhibit PtdIns 3-kinase with an IC50 of 1.3 microgram/ml (3.8 microM); inhibition appeared to be directed at the ATP-binding site of the kinase. Analogs of quercetin were investigated as PtdIns 3-kinase inhibitors, with the most potent ones exhibiting IC50 values in the range of 1.7-8.4 micrograms/ml. In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 > 30 micrograms/ml). Since quercetin has also been shown to inhibit other PtdIns and protein kinases, other chromones were evaluated as inhibitors of PtdIns 3-kinase without affecting PtdIns 4-kinase or selected protein kinases. One such compound, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (also known as 2-(4-morpholinyl)-8-phenylchromone, LY294002), completely and specifically abolished PtdIns 3-kinase activity (IC50 = 0.43 microgram/ml; 1.40 microM) but did not inhibit PtdIns 4-kinase or tested protein and lipid kinases. Analogs of LY294002 demonstrated a very selective structure-activity relationship, with slight changes in structure causing marked decreases in inhibition. LY294002 was shown to completely abolish PtdIns 3-kinase activity in fMet-Leu-Phe-stimulated human neutrophils, as well as inhibit proliferation of smooth muscle cells in cultured rabbit aortic segments. Since PtdIns 3-kinase appears to be centrally involved with growth factor signal transduction, the development of specific inhibitors against the kinase may be beneficial in the treatment of proliferative diseases as well as in elucidating the biological role of the kinase in cellular proliferation and growth factor response.
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            Type VII secretion--mycobacteria show the way.

            Abdallah M Abdallah, Nicolaas Gey van Pittius, Patricia DiGiuseppe Champion … (2007)
            Recent evidence shows that mycobacteria have developed novel and specialized secretion systems for the transport of extracellular proteins across their hydrophobic, and highly impermeable, cell wall. Strikingly, mycobacterial genomes encode up to five of these transport systems. Two of these systems, ESX-1 and ESX-5, are involved in virulence - they both affect the cell-to-cell migration of pathogenic mycobacteria. Here, we discuss this novel secretion pathway and consider variants that are present in various Gram-positive bacteria. Given the unique composition of this secretion system, and its general importance, we propose that, in line with the accepted nomenclature, it should be called type VII secretion.
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              The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue.

              T. Hsu, S. Hingley-Wilson, B. Chen … (2011)
              Tuberculosis remains a leading cause of death worldwide, despite the availability of effective chemotherapy and a vaccine. Bacillus Calmette-Guérin (BCG), the tuberculosis vaccine, is an attenuated mutant of Mycobacterium bovis that was isolated after serial subcultures, yet the functional basis for this attenuation has never been elucidated. A single region (RD1), which is absent in all BCG substrains, was deleted from virulent M. bovis and Mycobacterium tuberculosis strains, and the resulting DeltaRD1 mutants were significantly attenuated for virulence in both immunocompromised and immunocompetent mice. The M. tuberculosis DeltaRD1 mutants were also shown to protect mice against aerosol challenge, in a similar manner to BCG. Interestingly, the DeltaRD1 mutants failed to cause cytolysis of pneumocytes, a phenotype that had been previously used to distinguish virulent M. tuberculosis from BCG. A specific transposon mutation, which disrupts the Rv3874 Rv3875 (cfp-10 esat-6) operon of RD1, also caused loss of the cytolytic phenotype in both pneumocytes and macrophages. This mutation resulted in the attenuation of virulence in mice, as the result of reduced tissue invasiveness. Moreover, specific deletion of each transcriptional unit of RD1 revealed that three independent transcriptional units are required for virulence, two of which are involved in the secretion of ESAT-6 (6-kDa early secretory antigenic target). We conclude that the primary attenuating mechanism of bacillus Calmette-Guérin is the loss of cytolytic activity mediated by secreted ESAT-6, which results in reduced tissue invasiveness.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 12 August 2009
                Publication date (Electronic): 28 June 2009
                Publication date (Print): August 2009
                Publication date PMC-release: 1 February 2010
                Volume: 10
                Issue: 8
                Pages: 899-906
                Affiliations
                [1 ]Division of Rheumatology/Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
                [2 ]Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115
                Author notes
                [*]

                These authors contributed equally to this study.

                Corresponding authors: Heinz Remold, MD, PhD Department of Medicine Division of Rheumatology, Immunology and Allergy Brigham and Women's Hospital and Harvard Medical School Smith Research Building 1 Jimmy Fund Way Boston, MA 02115 hremold@ 123456rics.bwh.harvard.edu
                Samuel Behar, MD, PhD Department of Medicine Division of Rheumatology, Immunology and Allergy Brigham and Women's Hospital and Harvard Medical School Smith Research Building 1 Jimmy Fund Way Boston, MA 02115 sbehar@ 123456rics.bwh.harvard.edu
                Article
                Manuscript ID: nihpa119668
                DOI: 10.1038/ni.1758
                PMC ID: 2730354
                PubMed ID: 19561612
                SO-VID: 2a6a7979-476a-45fc-8401-886ecea590fc
                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI072143-03 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI050216-05 ||AI
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
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                ScienceOpen disciplines: Immunology

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