Apoptosis Genes in Human Alveolar Macrophages Infected with Virulent or Attenuated<i>Mycobacterium tuberculosis</i>

Spira, Avrum; Carroll, Joanne; Liu, Gang; Aziz, Zeeshan; Shah, Vishal; Kornfeld, Hardy; Keane, Joseph

doi:10.1165/rcmb.2002-0310oc

Cited by 89 publications

(72 citation statements)

References 39 publications

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“…Several in vitro studies have demonstrated that alveolar macrophages undergo apoptosis following infection with M. tuberculosis [2][3][4][5][6][7][8], and apoptosis of these infected macrophages may benefit the host by eliminating the favorable environment for bacterial growth [4,5]. Furthermore, these in vitro studies have also demonstrated that infected macrophage apoptosis was TNF-a dependent, and virulent strains, such as H37Rv, induce lesser macrophage apoptosis than the isogenic avirulent strain H37Ra [5].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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The kinetics of macrophage and T lymphocyte apoptosis were determined in a wellcharacterized mouse model of pulmonary tuberculosis, comparing strains of intermediate (H37Rv) and high virulence (Beijing strain, code 9501000). Both strains induced a high percentage of apoptotic activated macrophages at days 1 and 3 post infection, although this was twofold lower in Beijing-infected mice. Progressive pneumonia started at day 14 (Beijing) or 21 (H37Rv) post infection. Pneumonic areas contained numerous macrophages with vacuolated cytoplasm (VM). In H37Rv infection few VM were apoptotic (8.7% at day 60), and the percentage was even lower in Beijing infection (1.4% at day 28). A high percentage of VM expressed the anti-apoptotic molecule Bcl-2 (H37Rv, 83%; Beijing, 95%). Both strains induced a progressive increase of apoptotic Th1 lymphocytes, peaking at day 60 in H37Rv infection, or 28 in Beijing infection. The peak was twofold higher in the latter. VM had strong FasL immunostaining, and confocal microscopy showed numerous apoptotic Th1 cells closely associated with them, suggesting that VM might induce apoptosis of Th1 cells. These results support the hypothesis that apoptosis of macrophages is associated with protection, while apoptosis of Th1 cells favors disease progression, and is related to the virulence of the mycobacterial strain.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, using in vitro systems, it has been shown that virulent strains induce less macrophage apoptosis than non-virulent strains [5,6]. Tumor necrosis factor-alpha (TNF-a) and nitric oxide (NO) are the most important pro-apoptotic mediators in this process [6,7], while Bcl-2 is the most significant anti-apoptotic molecule [8].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…Several candidate genes have been proposed to be associated with susceptibility for pulmonary TB [46][47][48][49]. Using these candidate genes, the quest for polymorphisms associated with disseminated disease has begun.…”

Section: Host Geneticsmentioning

confidence: 99%

Tuberculous Meningitis in Adults: A Review of a Decade of Developments Focusing on Prognostic Factors for Outcome

2012

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Tuberculous meningitis (TBM) is the most severe form of TB. Despite treatment, mortality and long-term disability remain unacceptably high. Prevention, early recognition, diagnosis and treatment are fundamental to improving outcomes. However, an effective vaccine remains elusive, initial symptoms are nonspecific, and sensitive diagnostic tests are not available. There has been progress in our understanding of the immunopathology of TBM, and several factors have been found to be associated with susceptibility to infection, disease progression and clinical outcome. However, these have not yet impacted on treatment. Early treatment initiation and uninterrupted continuation, severity on presentation, seizures, stroke, cranial nerve involvement, cerebrospinal fluid cell count and lactate levels, hyponatreamia and coinfection with HIV are all found to be important prognostic factors for outcome. Pathogen lineage (Beijing genotype) and host genetics (polymorphisms in TLR2, TIRAP and LTA4H genes) can influence susceptibility to TBM. However, these findings have not yet impacted on treatment. Progress in vaccine development, opportunities for better diagnostic tests, novel insights into pathogenesis and an increasing evidence base for improving treatment should impact the current high mortality and morbidity, if translated to global and local guidelines.

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“…The relevance of intracellular growth to strain virulence is supported by recent studies indicating that so-called ''hypervirulent strains,'' identified by molecular fingerprinting as being responsible for outbreak ''clusters'' of active tuberculosis, grow more rapidly within human phagocytes than do nonclustered isolates (11,12). Although differences in the interactions of M. tuberculosis strains of varying virulence with human phagocytes have been assessed using focused gene expression arrays (13,14),…”

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confidence: 99%

Human Alveolar Macrophage Gene Responses toMycobacterium tuberculosisStrains H37Ra and H37Rv

Silver¹,

Walrath²,

Lee³

et al. 2009

Am J Respir Cell Mol Biol

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H37Rv and H37Ra have been widely used as models of virulent and avirulent strains, respectively, of Mycobacterium tuberculosis. Since the sequencing of H37Rv, microarrays have been used to investigate gene expression of M. tuberculosis strains under various conditions, and to compare gene expression of specific isolates of the organism. Because differences in the virulence of these organisms could also be manifest via their differential induction of host genes, we used Affymetrix Human Genome Arrays U133A and U133B to evaluate human alveolar macrophage (AM) responses to infection with H37Rv and H37Ra. H37Rv altered expression of far more genes than did H37Ra. Moreover, the genes induced by H37Rv to a greater extent than by H37Ra were predominantly associated with the development of effective immunity. H37Rv markedly increased expression of IL-23 p19, whereas neither organism significantly induced IL-12 p35 expression. Quantitative PCR confirmed that H37Rv induced significantly more AM p19 expression than did H37Ra. After low-level infection of both AM and peripheral blood monocytes (MN) with H37Rv, neither cell type produced IL-12 (by ELISA). In contrast, AM displayed significant IL-23 production in response to H37Rv, whereas MN did not. Our findings thus suggest an important role for IL-23 in human host responses to pulmonary infection with M. tuberculosis, and are consistent with epidemiologic and genetic studies that imply that H37Rv may not have unusual capacity to cause human disease.

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Apoptosis Genes in Human Alveolar Macrophages Infected with Virulent or AttenuatedMycobacterium tuberculosis

Cited by 89 publications

References 39 publications

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

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

Tuberculous Meningitis in Adults: A Review of a Decade of Developments Focusing on Prognostic Factors for Outcome

Human Alveolar Macrophage Gene Responses toMycobacterium tuberculosisStrains H37Ra and H37Rv

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