Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

Ríos-Barrera, Víctor Adolfo; Campos-Peña, Victoria; Aguilar‐León, Diana; Lascurain, Ledesma Ricardo; Meraz-Ríos, Marco Antonio; Moreno, José; Figueroa-Granados, Víctor; Hernández-Pando, Rogelio

doi:10.1002/eji.200535202

Cited by 65 publications

(54 citation statements)

References 25 publications

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“…However, FasL mRNA was higher in both CD14 1 and CD14 À cells from TB patients, suggesting a broad upregulation of this molecule in this cohort. This observation is consistent with earlier reports from human and murine M. tuberculosis infections [38,40,[42][43][44]. …”

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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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confidence: 93%

“…In addition to its role as an activating factor, TNF-a plays an important role in immunopathology [39] and cell death [40]. Cell death by apoptosis has been postulated as a potentially important method by which infected macrophages are removed in TB [41].…”

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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“…Bcl2 is involved in suppressing apoptosis and it has been implicated in apoptosis associated with infections; however, this gene was found outside the critical candidate region for Ity3 (Kroemer 1997;Rios-Barrera et al 2006).…”

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Molecular Genetic Analysis of Two Loci (Ity2andIty3) Involved in the Host Response to Infection With Salmonella Typhimurium Using Congenic Mice and Expression Profiling

et al. 2007

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Numerous genes have been identified to date that contribute to the host response to systemic Salmonella Typhimurium infection in mice. We have previously identified two loci, Ity2 and Ity3, that control survival to Salmonella infection in the wild-derived inbred MOLF/Ei mouse using a (C57BL/6J 3 MOLF/ Ei)F 2 cross. We validated the existence of these two loci by creating congenic mice carrying each quantitative trait locus (QTL) in isolation. Subcongenic mice generated for each locus allowed us to define the critical intervals underlying Ity2 and Ity3. Furthermore, expression profiling was carried out with the aim of identifying differentially expressed genes within the critical intervals as potential candidate genes. Genomewide expression arrays were used to interrogate expression differences in the Ity2 congenics, leading to the identification of a new candidate gene (Havcr2, hepatitis A virus cellular receptor 2). Interval-specific oligonucleotide arrays were created for Ity3, identifying one potential candidate gene (Chi3l1, chitinase 3-like 1) to be pursued further. The combination of the use of congenics in QTL confirmation and fine mapping and in the identification of candidate genes by expression profiling has been successful and represents a step toward quantitative gene(s) identification.

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“…It has been suggested that macrophage apoptosis represents a successful host immune response to M. tuberculosis infection in vivo (40,42). M. tuberculosis is an intracellular pathogen and, as such, this organism is dependent on the continuing survival of the host cell to provide it with a refuge in which to replicate.…”

Section: Discussionmentioning

confidence: 99%

A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response toMycobacterium tuberculosisInfection

et al. 2007

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Macrophages can undergo apoptosis after infection with Mycobacterium tuberculosis. This macrophage response deprives the bacillus of its niche cell and supports the host response through better antigen presentation. The intracellular pathways of apoptosis that elaborate this macrophage response are not well understood. To address this issue, we investigated the contribution of various apoptosis pathways to M. tuberculosis-induced macrophage cell death. We found that macrophages die in a caspase-independent manner after infection with M. tuberculosis (at multiplicities of infection ranging from 1 to 20). There was evidence for the involvement of both the mitochondria (cleavage of Bid) and the lysosomes (cathepsin-mediated DNA fragmentation) in this cell death pathway. Dying macrophages displayed several features typical of apoptosis, including DNA fragmentation, nuclear condensation, and exposure of phosphatidylserine on the plasma membrane. However, nuclear fragmentation was not observed, which suggests that M. tuberculosis-induced cell death differs in some respects from classical apoptosis. This novel mechanism of cell death was blocked by serine protease inhibitors. A better understanding of this protective macrophage response may direct new vaccine and treatment options.

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Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

Cited by 65 publications

References 25 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

Molecular Genetic Analysis of Two Loci (Ity2andIty3) Involved in the Host Response to Infection With Salmonella Typhimurium Using Congenic Mice and Expression Profiling

A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response toMycobacterium tuberculosisInfection

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