Cell death and inflammation during infection with the obligate intracellular pathogen, Chlamydia

Perfettini, Jean-Luc; Stahl, Lynn; Jungas, Thomas; Verbeke, Philippe; Ojcius, David M.

doi:10.1016/j.biochi.2003.08.006

Cited by 28 publications

(25 citation statements)

References 61 publications

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“…In contrast, other groups have reported that C. pneumoniae, C. trachomatis, and C. psittaci stimulate cell death in epithelial cells, macrophages, and other cell types (16,35,(37)(38)(39)43). Furthermore, other types of obligate intracellular gram-negative bacteria, such as Legionella longbeachae, have been shown to induce apoptosis in macrophages (34).…”

Section: Discussionmentioning

confidence: 95%

Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

Yaraei¹,

Campbell²,

Zhu

et al. 2005

Infect Immun

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Chlamydia pneumoniae is a common respiratory pathogen that is associated with an increased risk of cardiovascular disease. However, the mechanisms by which C. pneumoniae contributes to cardiovascular disease have not been determined yet. C. pneumoniae infection may accelerate the death of cells within atherosclerotic lesions and contribute to the formation of unstable lesions. To test this hypothesis, the impact of C. pneumoniae infection on the death of lipid-loaded mouse macrophages was investigated. It was observed that RAW 264.7 cells are highly susceptible to the toxic effects of oxidized low-density lipoprotein (LDL) and exhibit markers of cell death within 24 h of treatment with as little as 5 g/ml oxidized LDL. Subsequent infection with either live C. pneumoniae or heat-killed or UV-inactivated C. pneumoniae at a low multiplicity of infection for 24 to 72 h stimulated both additional binding of annexin V and the uptake of propidium iodide. Thus, C. pneumoniae augments the effects of oxidized LDL on cell death independent of a sustained infection. However, unlike oxidized LDL, C. pneumoniae infection does not activate caspase 3 or induce formation of the mitochondrial transition pore or the fragmentation of DNA, all of which are classical markers of apoptosis. Furthermore, primary bone marrow macrophages isolated from mice deficient in Toll-like receptor 2 (TLR-2) but not TLR-4 are resistant to C. pneumoniae-induced death. These data suggest that C. pneumoniae kills cells by a caspase-independent pathway and that the process is potentially mediated by activation of TLR-2.

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Section: Discussionmentioning

confidence: 95%

Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

Yaraei¹,

Campbell²,

Zhu

et al. 2005

Infect Immun

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“…Viruses and other obligate intracellular pathogens, such as Chlamydia sp. (45), have presumably evolved under considerable selective pressure to modulate apoptotic pathways, because premature death of the host cell would prevent the completion of their replication cycle. However, in some situations, such as virus egress, apoptosis may be beneficial, and many viruses have also evolved pro-apoptotic mechanisms (43).…”

Section: Discussionmentioning

confidence: 99%

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Knodler

Finlay

Steele‐Mortimer

2005

Journal of Biological Chemistry

215

213

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Invasion of epithelial cells by Salmonella enterica is mediated by bacterial "effector" proteins that are delivered into the host cell by a type III secretion system. Although primarily known for their roles in actin rearrangements and membrane ruffling, translocated effectors also affect host cell processes that are not directly associated with invasion. Here, we show that SopB/SigD, an effector with phosphoinositide phosphatase activity, has anti-apoptotic activity in Salmonellainfected epithelial cells. Salmonella induced the sustained activation of Akt/protein kinase B, a pro-survival kinase, in a SopB-dependent manner. Failure to activate Akt resulted in increased levels of apoptosis after infection with a sopB deletion mutant (⌬sopB). Furthermore, cells infected with wild type bacteria, but not the ⌬sopB strain, were protected from camptothecin-induced cleavage of caspase-3 and subsequent apoptosis. The anti-apoptotic activity of SopB was dependent on its phosphatase activity, because a catalytically inactive mutant was unable to protect cells from the effects of camptothecin. Finally, small interfering RNA was used to demonstrate the essential role of Akt in SopB-mediated protection against apoptosis. These results provide new insights into the mechanisms of apoptosis and highlight how bacterial effectors can intercept signaling pathways to manipulate host responses.

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“…Furthermore, circumstantial evidence indicates that mTORC1 inhibition may have additional beneficial effects in AIDS patients by limiting the replication of HIV and the detrimental effects of the virus on the target CD4 ϩ T lymphocytes by preventing cell syncytium formation and p53-triggered cell apoptosis. 46,47 Finally, the application of mTORC1 inhibitors to treat ARL would represent an alternative to the current regimens of multi-agent chemotherapy which not only display a plethora of severe toxicities, but are also rather ineffective in the AIDS patients, 48,49 even when combined with an anti-CD20 antibody. 48 …”

Section: Discussionmentioning

confidence: 99%

Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas

El-Salem

Raghunath

Marzec

et al. 2009

The American Journal of Pathology

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Using immunohistochemistry with antibodies against the phosphoserine residues in both S6rp and 4E binding protein 1, we identified the activation of the mammalian target of rapamycin (mTORC)1 pathway in 29 cases of AIDS-related lymphoma. These cases represented a diverse spectrum of histological types of nonHodgkin lymphoma (24 cases) and classic Hodgkin lymphoma (five cases). mTORC1 was also activated in the hyperplastic but not involuted follicles of HIV-associated lymphadenopathy in eight cases, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irrespective of either their reactive or malignant phenotype. We also found that in B-cell lines that represent diffuse large B-cell lymphoma, Burkitt lymphoma, Epstein-Barr virus-infected lymphocytes, and human herpesvirus 8-positive primary effusion lymphoma, inhibitors of Syk, MEK, and, seemingly , phosphoinositide 3 kinases suppressed mTORC1 activation , in particular when these inhibitors were used in combination. These findings indicate that AIDS-related lymphoma and other histologically similar types of lymphomas that are derived from transformed B lymphocytes may display clinical responses to inhibitors that directly target mTORC1 or , possibly , upstream activators of the mTORC1 pathway.

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Cell death and inflammation during infection with the obligate intracellular pathogen, Chlamydia

Cited by 28 publications

References 61 publications

Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

Chlamydia pneumoniaeAugments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas

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