NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection

Dawn R. Clifton, Rachel A. Goss, Sanjeev Sahni, Daniel Van Antwerp, Raymond B. Baggs, Victor J. Marder, David J. Silverman, Lee Ann Sporn

Research output: Contribution to journalArticle

185 Citations (Scopus)

Abstract

The possibility that bacteria may have evolved strategies to overcome host cell apoptosis was explored by using Rickettsia ricketsii, an obligate intracellular Gram-negative bacteria that is the etiologic agent of Rocky Mountain spotted fever. The vascular endothelial cell, the primary target cell during in vivo infection, exhibits no evidence of apoptosis during natural infection and is maintained for a sufficient time to allow replication and cell-to-cell spread prior to eventual death due to necrotic damage. Prior work in our laboratory demonstrated that R. ricketsii infection of several genes under its control. However, when R. ricketsii- induced activation of NF-κB was inhibited, apoptosis of infected but not uninfected endothelial cells repidly ensued. In addition, human embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit IκB that rendered NF-κB inactivatable also underwent apoptosis when infected, whereas infected wild-type human embryonic fiboblasts stably transfected with a superrepressor mutant inhibitory subunit IκB that rendered NF-κB inactivatable also underwent apoptosis when infected, whereas infected wild- type human embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell apoptosis via a mechanism dependent on NF-̄ activation. Apoptotic nuclear changes correlated with presence of intracellular organisms and thus this previously unrecognized proapoptic signal, masked by concomitant NF-κB activation, likely required intracellular infection. Our studies demonstrate that a bacterial organism can exert an antiapoptotic effect, thus modulating that host cell's apoptotic response to its own advantage by potentially allowing the host cell to remain as a site of infection.

Original languageEnglish (US)
Pages (from-to)4646-4651
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number8
DOIs
StatePublished - Apr 14 1998
Externally publishedYes

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Rickettsia Infections
Rickettsia rickettsii
Cell Survival
Apoptosis
Infection
Endothelial Cells
Fibroblasts
Rocky Mountain Spotted Fever
Rickettsia
Gram-Negative Bacteria
Bacteria

ASJC Scopus subject areas

  • Genetics
  • General

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NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection. / Clifton, Dawn R.; Goss, Rachel A.; Sahni, Sanjeev; Van Antwerp, Daniel; Baggs, Raymond B.; Marder, Victor J.; Silverman, David J.; Sporn, Lee Ann.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 8, 14.04.1998, p. 4646-4651.

Research output: Contribution to journalArticle

Clifton, Dawn R. ; Goss, Rachel A. ; Sahni, Sanjeev ; Van Antwerp, Daniel ; Baggs, Raymond B. ; Marder, Victor J. ; Silverman, David J. ; Sporn, Lee Ann. / NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection. In: Proceedings of the National Academy of Sciences of the United States of America. 1998 ; Vol. 95, No. 8. pp. 4646-4651.
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