Increased Bcl‐2 and Reduced Bax Expression in Infected Macrophages in Slowly Progressive Primary Murine <i>Mycobacterium tuberculosis</i> Infection

Mogga, S. J.; Mustafa, Tehmina; Sviland, Lisbet; Nilsen, Rune

doi:10.1046/j.1365-3083.2002.01140.x

Cited by 46 publications

(53 citation statements)

References 44 publications

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“…This hypothesis is compatible with the in vitro data already published showing inhibition of apoptosis in infected macrophages by virulent M. tuberculosis (but not avirulent mycobacteria) [27,28,55,[59][60][61][62][63]. It is also consistent with multiple reports suggesting that upregulation of Fas/FasL in vivo is specifically associated with T-cell death in TB [38,[64][65][66][67].…”

Section: Discussionsupporting

confidence: 91%

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic (''death receptor initiated'') pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-a and its receptors, Fas and FasL and proCaspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-a and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages -the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen. IntroductionDespite vaccination and drug treatment campaigns, tuberculosis (TB) causes an estimated 8-9 million new cases and mortality of 2-3 million deaths annually [1]. The TB epidemic is largely confined to developing countries, and is particularly serious in Sub-Saharan Africa [2], where it is fanned by the HIV epidemic. Despite the high mortality, most infected people do not immediately develop active disease, but become latently infected -though they may later reactivate their disease, if they become immunocompromised [3]. It is thought that perhaps as much as a third of the world's population is latently infected, [4] Eur. J. Immunol. 2010. 40: 291-301 DOI 10.1002 Clinical immunology 291 complicating control efforts by providing a reservoir from which new cases continually arise. Understanding immunity to Mycobacterium tuberculosis, so that more effective vaccines can be developed, is thus an international priority. The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both and . These two cytokines are essential for controlling mycobacterial infections [11][12][13] but in most cases, M. tuberculosis survives to establish a latent infection -which can rapidly reactivate if TNF-a production is blocked [14]. The precise mechanisms involved in this process are still only poorly known. We and others have previously shown that a bias towards IL-4 expression is associated with elevated risk of disease [15] while a bias towards the IL-4 antagonist IL-4d2, or towards IFN-g, is associated with reduced pathology, a better prognosis after infection, recovery after treatment and with ...

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Section: Discussionsupporting

confidence: 91%

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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“…The incomplete blocking of apoptosis in TNF-␣-cycloheximide-stimulated cells may have been due to inhibition of protein translation of transfected Bcl2 by cycloheximide. Interestingly, mycobacteria persisting in human macrophages upregulate Bcl2 to prolong survival of their host cells (33).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggested that antiapoptotic Bcl2 proteins play an impor- (33). Proapoptotic Bax has been found to be cleaved by calpain and to integrate in mitochondrial membranes to initiate programmed cell death (3), whereas proapoptotic Bid could be cleaved by caspase 8 and inhibit Bcl2 function (12).…”

Section: S Pneumoniae Induces Apoptosis In Human Alveolar Epithelialmentioning

confidence: 99%

Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium

et al. 2004

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Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia and one of the most common causes of death due to infectious diseases in industrialized countries. Lung epithelium lines the airways and constitutes the first line of innate defense against respiratory pathogens. Little is known about the molecular interaction of pneumococci with lung epithelial cells. Apoptosis of lung epithelium is involved in some bacterial lung infections. In this study different pneumococcal strains specifically induced either apoptotic or necrotic death of human alveolar and bronchial epithelial cells. Pneumococcus-induced apoptosis did not depend on the virulence factors pneumolysin and H 2 O 2 . Apoptotic cells showed increased activity of caspases 6, 8, and 9 but not increased activity of caspase 3. Moreover, programmed cell death could be strongly reduced by a caspase 6 inhibitor and a pan-caspase inhibitor. Inhibitors of calpain and chymotrypsin-and trypsin-like proteases also reduced pneumococcus-induced apoptosis. Furthermore, pneumococcus-infected human alveolar epithelial cells showed Bid cleavage and reduced levels of Bcl2 and Bax. Overexpression of Bcl2 in these cells reduced apoptosis significantly. Thus, pneumococci induced apoptosis of human alveolar and bronchial epithelial cells. Programmed cell death was executed by caspase 6 and noncaspase proteases, but not by caspase 3, and could be blocked by overexpression of Bcl2.

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“…It has been demonstrated that apoptosis, but not necrosis, is associated with killing of intracellular mycobacteria [2]. Thus, it has been hypothesized that inhibiting apoptosis of macrophages might be a survival strategy for virulent mycobacteria [3][4][5][6]. In vitro studies have shown that virulent mycobacterial strains induce less apoptosis of macrophages than non-virulent strains [7,8], but this has not been demonstrated in vivo in humans; which mycobacterial components are involved in the inhibition of apoptosis are not known either.…”

Section: Introductionmentioning

confidence: 99%

“…We have shown earlier in murine lung lesions that M. tuberculosis strain H37Rv can influence the expression of apoptosis regulatory proteins by causing increased expression of FasL and Bcl-2 on the infected macrophages. This allows mycobacteria to inhibit apoptosis of the infected cells through increased expression of Bcl-2, and these cells will then escape activation and killing by Fas-expressing lymphocytes by their increased expression of FasL [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response

Mustafa

Wiker

Mørkve

et al. 2007

Clinical and Experimental Immunology

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SummaryInhibition of apoptosis of infected macrophages by pathogenic mycobacteria is suggested to be an important virulence mechanism, but little is known about the mycobacterial proteins involved in the inhibition of apoptosis. In this study we investigated differences in apoptosis and immune response and their correlation with the expression of Mycobacterium tuberculosis complexspecific secretory protein

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Increased Bcl‐2 and Reduced Bax Expression in Infected Macrophages in Slowly Progressive Primary Murine Mycobacterium tuberculosis Infection

Cited by 46 publications

References 44 publications

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

Streptococcus pneumoniae-Induced Caspase 6-Dependent Apoptosis in Lung Epithelium

Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response

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