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1.
J Immunol ; 191(7): 3514-8, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23997220

RESUMO

Mycobacterium tuberculosis extracellular DNA gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this extracellular DNA of M. tuberculosis does not induce activation of the AIM2 inflammasome because AIM2 recognizes cytosolic DNA. In this study, we show that nonvirulent mycobacteria such as Mycobacterium smegmatis induce AIM2 inflammasome activation, which is dependent on their strong induction of IFN-ß production. In contrast, M. tuberculosis, but not an ESX-1-deficient mutant, inhibits the AIM2 inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that M. tuberculosis inhibits IFN-ß production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of M. tuberculosis that involves the ESX-1-dependent, direct or indirect, suppression of the host cell AIM2 inflammasome activation during infection.


Assuntos
Sistemas de Secreção Bacterianos/fisiologia , Inflamassomos/metabolismo , Interferon beta/metabolismo , Interleucina-1beta/metabolismo , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Proteínas Nucleares/metabolismo , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética
2.
BMC Microbiol ; 10: 237, 2010 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20831789

RESUMO

BACKGROUND: The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like, Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, non-pathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate immune response by the non-pathogenic mycobacterial species. RESULTS: A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from non-pathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the whole bacteria. Indeed, PI-LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded by secreting large amounts of TNF upon infection with non-pathogenic but not facultative-pathogenic mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient to induce host cell apoptosis. CONCLUSION: These results demonstrate a much stronger induction of the innate immune response by non-pathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine induction. These observations lend support to the hypothesis that the strong induction of the innate immune response is a major reason for the lack of pathogenicity in fast-growing mycobacteria.


Assuntos
Apoptose , Caspase 3/imunologia , Interações Hospedeiro-Patógeno , Infecções por Mycobacterium/fisiopatologia , Mycobacterium/fisiologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/imunologia , Animais , Linhagem Celular , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium/patogenicidade , Infecções por Mycobacterium/enzimologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia
3.
Infect Immun ; 76(12): 5478-87, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18852239

RESUMO

The ESX-1 secretion system plays a critical role in the virulence of M. tuberculosis and M. marinum, but the precise molecular and cellular mechanisms are not clearly defined. Virulent M. marinum is able to escape from the Mycobacterium-containing vacuole (MCV) into the host cell cytosol, polymerize actin, and spread from cell to cell. In this study, we have examined nine M. marinum ESX-1 mutants and the wild type by using fluorescence and electron microscopy detecting MCV membranes and actin polymerization. We conclude that ESX-1 plays an essential role in M. marinum escape from the MCV. We also show that the ESX-1 mutants acquire the ability to polymerize actin after being artificially delivered into the macrophage cytosol by hypotonic shock treatment, indicating that ESX-1 is not directly involved in initiation of actin polymerization. We provide evidence that M. marinum induces membrane pores approximately 4.5 nm in diameter, and this activity correlates with ESAT-6 secretion. Importantly, purified ESAT-6, but not the other ESX-1-secreted proteins, is able to cause dose-dependent pore formation in host cell membranes. These results suggest that ESAT-6 secreted by M. marinum ESX-1 could play a direct role in producing pores in MCV membranes, facilitating M. marinum escape from the vacuole and cell-to-cell spread. Our study provides new insight into the mechanism by which ESX-1 secretion and ESAT-6 enhance the virulence of mycobacterial infection.


Assuntos
Proteínas de Bactérias/metabolismo , Membrana Celular/microbiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/patogenicidade , Vacúolos/microbiologia , Animais , Western Blotting , Membrana Celular/metabolismo , Eritrócitos/microbiologia , Macrófagos/microbiologia , Camundongos , Microscopia Eletrônica de Transmissão , Infecções por Mycobacterium não Tuberculosas/metabolismo , Mycobacterium marinum/metabolismo , Ovinos , Vacúolos/metabolismo
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