Characterization of Host Cell Death Induced by Chlamydia trachomatis

ABSTRACT Chlamydia are obligate intracellular bacteria that modulate apoptosis of the host cell. Strikingly, chlamydial infection has been reported both to inhibit and to induce apoptosis. Although the ability to inhibit apoptosis has been corroborated by the identification of cellular targets, confirmation of cell death induction has been complicated by a mixture of apoptotic features and atypical cell death during infection, as well as by differences in the experimental techniques used to measure cell death. Here we use a panel of well-established approaches in the study of apoptosis to define the form of cell death induced by Chlamydia trachomatis infection. Infected cells displayed apoptotic features such as nuclear condensation and fragmentation, as well as positive TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining. Fragmentation of genomic DNA occurred, but was atypical. Clear evidence against the activation of effector caspases was found. Nuclear changes were measured in fibroblasts lacking one or both of the effectors of mitochondrial apoptosis, Bax and Bak. A slight reduction in nuclear changes was observed in Bax-deficient cells and in Bax/Bak double-deficient cells. Most surprisingly, this reduction was almost complete in Bak-deficient cells. Finally, dying infected cells were efficiently taken up by professional phagocytes, suggesting that Chlamydia-induced host-cell death could play a role in the immune response. In conclusion, chlamydial infection can induce cell death. Although Chlamydia-induced cell death has certain morphological features of apoptosis, it does not result from activation of the apoptotic pathway.

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Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death

Cell Reports ◽

10.1016/j.celrep.2017.04.058 ◽

2017 ◽

Vol 19 (7) ◽

pp. 1406-1417 ◽

Cited By ~ 41

Author(s):

Mary M. Weber ◽

Jennifer L. Lam ◽

Cheryl A. Dooley ◽

Nicholas F. Noriea ◽

Bryan T. Hansen ◽

...

Keyword(s):

Cell Death ◽

Chlamydia Trachomatis ◽

Membrane Proteins ◽

Host Cell ◽

Inclusion Membrane ◽

Host Cell Death ◽

Membrane Lysis ◽

Inclusion Membrane Proteins

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Involvement of Caspase-9 in the Inhibition of Necrosis of RAW 264 Cells Infected with Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.01639-06 ◽

2007 ◽

Vol 75 (6) ◽

pp. 2894-2902 ◽

Cited By ~ 7

Author(s):

Ryosuke Uchiyama ◽

Ikuo Kawamura ◽

Takao Fujimura ◽

Michiko Kawanishi ◽

Kohsuke Tsuchiya ◽

...

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Specific Inhibitor ◽

Host Cells ◽

Ros Generation ◽

Caspase 9 ◽

Host Cell Death ◽

Intracellular Ros ◽

Infected Cells

ABSTRACT In order to know how caspases contribute to the intracellular fate of Mycobacterium tuberculosis and host cell death in the infected macrophages, we examined the effect of benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethane (z-VAD-fmk), a broad-spectrum caspase inhibitor, on the growth of M. tuberculosis H37Rv in RAW 264 cells. In the cells treated with z-VAD-fmk, activation of caspase-8, caspase-3/7, and caspase-9 was clearly suppressed, and DNA fragmentation of the infected cells was also reduced. Under this experimental condition, it was found that the treatment markedly inhibited bacterial growth inside macrophages. The infected cells appeared to undergo cell death of the necrosis type in the presence of z-VAD-fmk. We further found that z-VAD-fmk treatment resulted in the generation of intracellular reactive oxygen species (ROS) in the infected cells. By addition of a scavenger of ROS, the host cell necrosis was inhibited and the intracellular growth of H37Rv was significantly restored. Among inhibitors specific for each caspase, only the caspase-9-specific inhibitor enhanced the generation of ROS and induced necrosis of the infected cells. Furthermore, we found that severe necrosis was induced by infection with H37Rv but not H37Ra in the presence of z-VAD-fmk. Caspase-9 activation was also detected in H37Rv-infected cells, but H37Ra never induced such caspase-9 activation. These results indicated that caspase-9, which was activated by infection with virulent M. tuberculosis, contributed to the inhibition of necrosis of the infected host cells, presumably through suppression of intracellular ROS generation.

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High-frequency interconversion of turbid and clear plaque strains of bacteriophage f1 and associated host cell death

Canadian Journal of Microbiology ◽

10.1139/w00-068 ◽

2000 ◽

Vol 46 (9) ◽

pp. 841-847 ◽

Cited By ~ 9

Author(s):

Mei-Yin Kuo ◽

Mei-Kwei Yang ◽

Wen-Ping Chen ◽

Tsong-Teh Kuo

Keyword(s):

Cell Death ◽

Host Cell ◽

Time Course ◽

Bacterial Cells ◽

Wild Type ◽

Clear Plaque ◽

Host Cell Death ◽

Rna And Protein Synthesis ◽

Filamentous Bacteriophages ◽

Infected Cells

Under normal cultivation conditions, a mixture of turbid and clear plaques is often apparent in cultures of bacterial cells infected with filamentous bacteriophages. Beginning with a culture of wild-type filamentous phage f1, which itself produces turbid plaques, a clear plaque strain (c1) was isolated. From c1, the turbid plaque strain t1 was isolated; from t1, the clear plaque strain c2 was isolated; and from c2, the turbid plaque strain t2 was isolated. Each of these strains was generated with a frequency of approximately 1 × 10-4. Although filamentous phages have been thought not to induce host cell death, both turbid and clear plaque strains of f1 killed host bacteria. Plating of bacterial cells 1 h after infection revealed that colonies produced by cells infected with either wild-type f1 or strain c2 were smaller than those derived from uninfected cells, and that colony formation by infected cells was reduced by 15% and 38%, respectively. The time course of bacterial growth revealed that, at 4 h after infection, the number of CFU per milliliter of culture of cells infected with wild-type f1 or with strain c2 was reduced by 27% and 95%, respectively, compared with that for uninfected cells. Microculture analysis also revealed that the percentages of nondividing cells in f1 or c2 infected were 19% and 52%, respectively, 4 h after infection with wild-type f1 or with strain c2; no such cells were detected in cultures of uninfected cells. Negative staining and electron microscopy showed that 20% and 61% of cells infected with wild-type f1 or with strain c2 were dead 4 h postinfection. Finally, although the rates of DNA synthesis were similar for infected and uninfected cells, the rates of RNA and protein synthesis were markedly reduced in infected cells.Key words: Escherichia coli, bacteriophages, turbid plaque, clear plaque.

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Faculty Opinions recommendation of Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13988977.15445089 ◽

2012 ◽

Author(s):

Thierry Soldati ◽

Sonia Arafah

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Host Cell Death

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Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

Cell Death Discovery ◽

10.1038/s41420-020-00366-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ayushi Chaurasiya ◽

Swati Garg ◽

Ashish Khanna ◽

Chintam Narayana ◽

Ved Prakash Dwivedi ◽

...

Keyword(s):

Cell Death ◽

Host Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Malaria Parasite ◽

Host Cells ◽

Nicotinamide Adenine ◽

Targeted Therapeutics ◽

Nad Metabolism ◽

Host Cell Death ◽

Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

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Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis

PLoS Pathogens ◽

10.1371/journal.ppat.0030161 ◽

2007 ◽

Vol 3 (11) ◽

pp. e161 ◽

Cited By ~ 133

Author(s):

Tessa Bergsbaken ◽

Brad T Cookson

Keyword(s):

Cell Death ◽

Host Cell ◽

Macrophage Activation ◽

Infected Host ◽

Infected Host Cell ◽

Caspase 1 ◽

Host Cell Death

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Kinetic Effect of Silkworm Hemolymph on the Delayed Host Cell Death in an Insect Cell-Baculovirus System

Biotechnology Progress ◽

10.1021/bp990093s ◽

1999 ◽

Vol 15 (6) ◽

pp. 1028-1032 ◽

Cited By ~ 39

Author(s):

W.J. Rhee ◽

E.J. Kim ◽

T.H. Park

Keyword(s):

Cell Death ◽

Host Cell ◽

Insect Cell ◽

Kinetic Effect ◽

Silkworm Hemolymph ◽

Host Cell Death ◽

Baculovirus System

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TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

Infection and Immunity ◽

10.1128/iai.00044-14 ◽

2014 ◽

Vol 82 (5) ◽

pp. 2068-2078 ◽

Cited By ~ 16

Author(s):

Christopher R. Doyle ◽

Ji-An Pan ◽

Patricio Mena ◽

Wei-Xing Zong ◽

David G. Thanassi

Keyword(s):

Cell Death ◽

Immune Responses ◽

Host Cell ◽

Francisella Tularensis ◽

Vaccine Strain ◽

Live Vaccine ◽

Live Vaccine Strain ◽

Type I ◽

Content Type ◽

Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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