Mycobacterium tuberculosis expressing phospholipase C subverts PGE2 synthesis and induces necrosis in alveolar macrophages

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Abstract

Background

Phospholipases C (PLCs) are virulence factors found in several bacteria. In Mycobacterium tuberculosis (Mtb) they exhibit cytotoxic effects on macrophages, but the mechanisms involved in PLC-induced cell death are not fully understood. It has been reported that induction of cell necrosis by virulent Mtb is coordinated by subversion of PGE ₂, an essential factor in cell membrane protection.

Results

Using two Mtb clinical isolates carrying genetic variations in PLC genes, we show that the isolate 97-1505, which bears plcA and plcB genes, is more resistant to alveolar macrophage microbicidal activity than the isolate 97-1200, which has all PLC genes deleted. The isolate 97-1505 also induced higher rates of alveolar macrophage necrosis, and likewise inhibited COX-2 expression and PGE ₂ production. To address the direct effect of mycobacterial PLC on cell necrosis and PGE ₂ inhibition, both isolates were treated with PLC inhibitors prior to macrophage infection. Interestingly, inhibition of PLCs affected the ability of the isolate 97-1505 to induce necrosis, leading to cell death rates similar to those induced by the isolate 97-1200. Finally, PGE ₂ production by Mtb 97-1505-infected macrophages was restored to levels similar to those produced by 97-1200-infected cells.

Conclusions

Mycobacterium tuberculosis bearing PLCs genes induces alveolar macrophage necrosis, which is associated to subversion of PGE ₂ production.

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Most cited references 42

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Revisiting the role of the granuloma in tuberculosis.

Lalita Ramakrishnan (2012)

The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries--from imaging studies coupled with genetic manipulations--that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases.

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Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy?

Maziar Divangahi, Heinz G. Remold, Heinz G. Remold (2010)

Virulent Mycobacterium tuberculosis inhibits apoptosis and triggers necrosis of host macrophages to evade innate immunity and delay the initiation of adaptive immunity. By contrast, attenuated M. tuberculosis induces macrophage apoptosis, an innate defence mechanism that reduces bacterial viability. In this Opinion article, we describe how virulent M. tuberculosis blocks production of the eicosanoid lipid mediator prostaglandin E(2) (PGE(2)). PGE(2) production by infected macrophages prevents mitochondrial damage and initiates plasma membrane repair, two processes that are crucial for preventing necrosis and inducing apoptosis. Thus, M. tuberculosis-mediated modulation of eicosanoid production determines the death modality of the infected macrophage, which in turn has a substantial impact on the outcome of infection.

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Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair

Maziar Divangahi, Minjian Chen, Huixian Gan … (2009)

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 E2 (PGE2), which regulates synaptotagmin 7, the Ca++ sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A4 (LXA4), which blocks PGE2 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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Author and article information

Contributors

Patricia A Assis

Milena S Espíndola

Francisco WG Paula-Silva

Wendy M Rios

Priscilla AT Pereira

Sylvia C Leão

Célio L Silva

Lúcia H Faccioli

Journal

Journal ID (nlm-ta): BMC Microbiol

Journal ID (iso-abbrev): BMC Microbiol

Title: BMC Microbiology

Publisher: BioMed Central

ISSN (Electronic): 1471-2180

Publication date Collection: 2014

Publication date (Electronic): 19 May 2014

Volume: 14

Page: 128

Affiliations

[1 ]Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av Cafe, s/n, Ribeirão Preto, SP 14040-903, Brazil

[2 ]Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil

[3 ]Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

Article

Publisher ID: 1471-2180-14-128

DOI: 10.1186/1471-2180-14-128

PMC ID: 4057917

PubMed ID: 24886263

SO-VID: 7372c115-7503-4f58-b043-90bb907820dc

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.