Nuclear factor κB protects against host cell apoptosis during Rickettsia rickettsii infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity

Suresh G. Joshi, Charles W. Francis, David J. Silverman, Sanjeev Sahni

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4127-4136
Number of pages10
JournalInfection and Immunity
Volume71
Issue number7
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

Fingerprint

Rickettsia Infections
Rickettsia rickettsii
Effector Caspases
Apoptosis
Caspase 9
Infection
Caspase 8
Caspase 3
Endothelial Cells
Rocky Mountain Spotted Fever
Caspase 6
Caspase 7
Cytoprotection
Poly(ADP-ribose) Polymerases
Vascular Endothelium
DNA Fragmentation
Caspases
Cytochromes c
Membrane Potentials
Cell Death

ASJC Scopus subject areas

  • Immunology

Cite this

Nuclear factor κB protects against host cell apoptosis during Rickettsia rickettsii infection by inhibiting activation of apical and effector caspases and maintaining mitochondrial integrity. / Joshi, Suresh G.; Francis, Charles W.; Silverman, David J.; Sahni, Sanjeev.

In: Infection and Immunity, Vol. 71, No. 7, 01.07.2003, p. 4127-4136.

Research output: Contribution to journalArticle

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AB - 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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