Evidence for apoptosis of human macrophage-like HL-60 cells by Legionella pneumophila infection

Müller, Anne; Hacker, Jörg; Brand, Bettina

doi:10.1128/iai.64.12.4900-4906.1996

Cited by 112 publications

(52 citation statements)

References 41 publications

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“…Numerous pathogens modulate the host apoptotic pathways by distinct mechanisms that trigger the extrinsic or intrinsic pathways of apoptosis; both of which converge on the activation of caspase-3, which is the executioner of apoptosis (Gao and Abu Kwaik, 2000a;Wang et al, 2005). Under low multiplicity of infection (moi), L. pneumophila induces a Dot/Icm-dependent activation of caspase-3 during early stages of infection independent of the classical extrinsic and intrinsic signalling pathways of apoptosis, but high moi triggers the intrinsic pathway (Muller et al, 1996;Gao and Abu Kwaik, 1999;Neumeister et al, 2002;Zink et al, 2002;Molmeret et al, 2004b;Abu-Zant et al, 2005;Fischer et al, 2006). Early activation of caspase-3 by L. pneumophila in human macrophages has been shown to be required for evasion of the endosomal-lysosomal pathway (Molmeret et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic signalling by the Dot/Icm secretion system ofL. pneumophila

Abu-Zant

Jones

Asare

et al. 2006

Cellular Microbiology

128

179

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SummaryThe Dot/Icm type IV secretion system of Legionella pneumophila triggers robust activation of caspase-3 during early and exponential stages of proliferation within human macrophages, but apoptosis is delayed till late stages of infection, which is novel. As caspase-3 is the executioner of the cell, we tested the hypothesis that L. pneumophila triggers antiapoptotic signalling within the infected human macrophages to halt caspase-3 from dismantling the cells. Here we show that during early and exponential replication, L. pneumophila-infected human monocyte-derived macrophages (hMDMs) exhibit a remarkable resistance to induction of apoptosis, in a Dot/Icm-dependent manner. Microarray analyses and real-time PCR reveal that during exponential intracellular replication, L. pneumophila triggers upregulation of 12 anti-apoptotic genes that are linked to activation of the nuclear transcription factor kappa-B (NF-kB). Our data show that L. pneumophila induces a Dot/Icm-dependent sustained nuclear translocation of the p50 and p65 subunits of NF-kB during exponential intracellular replication. Bacterial entry is essential both for the anti-apoptotic phenotype of infected hMDMs and for nuclear translocation of the p65. Using p65 -/-and IKKa -/-b -/-double knockout mouse embryonic fibroblast cell lines, we show that nuclear translocation of NF-kB is required for the resistance of L. pneumophila-infected cells to apoptosis-inducing agents. In addition, the L. pneumophila-induced nuclear translocation of NF-kB requires the activity of IKKa and/or IKKb. We conclude that although the Dot/Icm secretion system of L. pneumophila elicits an early robust activation of caspase-3 in human macrophages, it triggers a strong anti-apoptotic signalling cascade mediated, at least in part by NF-kB, which renders the cells refractory to external potent apoptotic stimuli.

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Section: Introductionmentioning

confidence: 99%

Anti-apoptotic signalling by the Dot/Icm secretion system ofL. pneumophila

Abu-Zant

Jones

Asare

et al. 2006

Cellular Microbiology

128

179

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“…Upon formation of this intracellular niche, L. pneumophila can multiply to high numbers, eventually lysing the host cell and spreading to other macrophages. Late in infection, apoptosis can be triggered in host cells, which may contribute to escape of the bacteria and initiation of subsequent rounds of infection (Muller et al, 1996;Walz et al, 2000;Abu-Zant et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Legionella pneumophila IcmS–LvgA protein complex is important for Dot/Icm‐dependent intracellular growth

Vincent

Vogel²

2006

Molecular Microbiology

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SummaryMany bacterial pathogens require a functional type IV secretion system (T4SS) for virulence. Legionella pneumophila, the causative agent of Legionnaires' disease, employs the Dot/Icm T4SS to inject a large number of protein substrates into its host, thereby altering phagosome trafficking. The L. pneumophila T4SS substrate SdeA has been shown to require the accessory factor IcmS for its export. IcmS, defined as a type IV adaptor, exists as a heterodimer with IcmW and this complex functions in a manner similar to a type III secretion chaperone. Here we report an interaction between IcmS and the previously identified virulence factor LvgA. Similar to the icmS mutant, the lvgA mutant appears to assemble a fully functional Dot/Icm complex. Both LvgA and IcmS are small, acidic proteins localized to the cytoplasm and are not exported by the Dot/Icm system, suggesting they form a novel type IV adaptor complex. Inactivation of lvgA causes a minimal defect in growth in the human monocytic cell line U937 and the environmental host Acanthamoeba castellanii. However, the lvgA mutant was severely attenuated for intracellular growth of L. pneumophila in mouse macrophages, suggesting LvgA may be a critical factor that confers host specificity.

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“…Legionella pneumophila also induces apoptosis in host macrophages (Müller et al, 1996), a process which appears to utilize the caspase pathway (Gao and Abu Kwaik, 1999), which might represent another exit strategy. Several effector proteins affect caspase-3-dependent apoptosis, balancing pro-and anti-apoptotic signalling (Zhu et al, 2013).…”

Section: Exit Of L Pneumophila From Phagocytesmentioning

confidence: 99%

The natural alternative: protozoa as cellular models forLegionellainfection

2013

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SummaryThe severe pneumonia known as Legionnaires' disease occurs following infection by the Gramnegative bacterium Legionella pneumophila. Normally resident in fresh-water sources, Legionella are subject to predation by eukaryotic phagocytes such as amoeba and ciliates. To counter this, L. pneumophila has evolved a complex system of effector proteins which allow the bacteria to hijack the phagocytic vacuole, hiding and replicating within their erstwhile killers. These same mechanisms allow L. pneumophila to hijack another phagocyte, lung-based macrophages, which thus avoids a vital part of the immune system and leads to infection. The course of infection can be divided into five main categories: pathogen uptake, formation of the replication-permissive vacuole, intracellular replication, host cell response, and bacterial exit. L. pneumophila effector proteins target every stage of this process, interacting with secretory, endosomal, lysosomal, retrograde and autophagy pathways, as well as with mitochondria. Each of these steps can be studied in protozoa or mammalian cells, and the knowledge gained can be readily applied to human pathogenicity. Here we describe the manner whereby L. pneumophila infects host protozoa, the various techniques which are available to analyse these processes and the implications of this model for Legionella virulence and the pathogenesis of Legionnaires' disease.

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Evidence for apoptosis of human macrophage-like HL-60 cells by Legionella pneumophila infection

Cited by 112 publications

References 41 publications

Anti-apoptotic signalling by the Dot/Icm secretion system ofL. pneumophila

Anti-apoptotic signalling by the Dot/Icm secretion system ofL. pneumophila

The Legionella pneumophila IcmS–LvgA protein complex is important for Dot/Icm‐dependent intracellular growth

The natural alternative: protozoa as cellular models forLegionellainfection

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