Macrophage apoptosis in host immunity to mycobacterial infections

Fairbairn, Ian P.

doi:10.1042/bst0320496

Cited by 37 publications

(25 citation statements)

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“…Cell death by apoptosis has been postulated as a potentially important method by which infected macrophages are removed in TB [41]. We therefore examined some of the other factors involved in the FADD pathway of cell death, which is activated by FasL and TNF-a.…”

Section: Assessment Of Production Of Fas and Fasl In Different Clinicmentioning

confidence: 99%

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: Assessment Of Production Of Fas and Fasl In Different Clinicmentioning

confidence: 99%

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

et al. 2009

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“…4 Stimulation of host macrophage apoptosis eliminates a potential site for future proliferation and destroys the infecting bacteria. 5 It has been suggested that phagocytosis of apoptotic bodies, sequestering pathogens, permits more efficient fusion of the phagosome with the lysosome resulting in the digestion of the pathogen. 6 Engulfment of dying macrophages by dendritic cells additionally promotes antigen presentation to T cells, linking innate and adaptive immunity.…”

Section: Significance Of Cell Death During Infectionmentioning

confidence: 99%

Cell death in the host response to infection

2008

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“…2,3 Furthermore, apoptotic macrophages are critical for inducing adaptive immune responses, as apoptotic vesicles containing mycobacteria are phagocytized by nearby antigen-presenting cells and presented to CD8 1 T cells. 4,5 Apoptosis of macrophages in this setting is partially tumor-necrosis factor-dependent. 6 Pathogenic MTB is reported to combat apoptosis through various mechanisms, including switching the cell death mode to necrosis and inactivating tumor-necrosis factor signaling.…”

Section: Introductionmentioning

confidence: 99%