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Journal article
Nuclear Factor κB Protects against Host Cell Apoptosis during Rickettsia rickettsii Infection by Inhibiting Activation of Apical and Effector Caspases and Maintaining Mitochondrial Integrity
Infection and immunity, v 71(7), pp 4127-4136
01 Jul 2003
PMID: 12819104
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Apoptotic host cell death is a critical determinant in the progression of microbial infections and outcome of resultant diseases. The potentially fatal human infection caused by
Rickettsia rickettsii,
the etiologic agent of Rocky Mountain spotted fever, involves the vascular endothelium of various organ systems of the host. Earlier studies have shown that survival of endothelial cells (EC) during this infection depends on their ability to activate the transcription factor nuclear factor κB (NF-κB). Here, we investigated the involvement of caspase cascades and associated signaling pathways in regulation of host cell apoptosis by NF-κB. Infection of cultured human EC with
R. rickettsii
with simultaneous inhibition of NF-κB induced the activation of apical caspases 8 and 9 and also the executioner enzyme, caspase 3, whereas infection alone had no significant effect. Inhibition of either caspase-8 or caspase-9 with specific cell-permeating peptide inhibitors caused a significant decline in the extent of apoptosis, confirming their importance. The peak caspase-3 activity occurred at 12 h postinfection and led to cleavage of poly(ADP-ribose) polymerase, followed by DNA fragmentation and apoptosis. However, the activities of caspases 6 and 7, other important downstream executioners, remained unchanged. Caspase-9 activation was mediated through the mitochondrial pathway of apoptosis, as evidenced by loss of transmembrane potential and cytoplasmic release of cytochrome
c.
These findings suggest that activation of NF-κB is required for maintenance of mitochondrial integrity of host cells and protection against infection-induced apoptotic death by preventing activation of caspase-9- and caspase-8-mediated pathways. Targeted inhibition of NF-κB may therefore be exploited to enhance the clearance of infections with
R. rickettsii
and other intracellular pathogens with similar survival strategies.
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Details
- Title
- Nuclear Factor κB Protects against Host Cell Apoptosis during Rickettsia rickettsii Infection by Inhibiting Activation of Apical and Effector Caspases and Maintaining Mitochondrial Integrity
- Creators
- Suresh G. Joshi - University of RochesterCharles W. Francis - University of RochesterDavid J. Silverman - University of Maryland, BaltimoreSanjeev K. Sahni - University of Rochester
- Publication Details
- Infection and immunity, v 71(7), pp 4127-4136
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000183797200058
- Scopus ID
- 2-s2.0-0038648686
- Other Identifier
- 991021448187304721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Infectious Diseases