{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:48:28Z","timestamp":1790048908239,"version":"4.0.1"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2003,7,1]],"date-time":"2003-07-01T00:00:00Z","timestamp":1057017600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2003,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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\n            <jats:italic>Rickettsia rickettsii,<\/jats:italic>\n            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 \u03baB (NF-\u03baB). Here, we investigated the involvement of caspase cascades and associated signaling pathways in regulation of host cell apoptosis by NF-\u03baB. Infection of cultured human EC with\n            <jats:italic>R. rickettsii<\/jats:italic>\n            with simultaneous inhibition of NF-\u03baB 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\n            <jats:italic>c.<\/jats:italic>\n            These findings suggest that activation of NF-\u03baB 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-\u03baB may therefore be exploited to enhance the clearance of infections with\n            <jats:italic>R. rickettsii<\/jats:italic>\n            and other intracellular pathogens with similar survival strategies.\n          <\/jats:p>","DOI":"10.1128\/iai.71.7.4127-4136.2003","type":"journal-article","created":{"date-parts":[[2003,6,21]],"date-time":"2003-06-21T16:09:13Z","timestamp":1056211753000},"page":"4127-4136","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":67,"title":["Nuclear Factor \u03baB Protects against Host Cell Apoptosis during\n            <i>Rickettsia rickettsii<\/i>\n            Infection by Inhibiting Activation of Apical and Effector Caspases and Maintaining Mitochondrial Integrity"],"prefix":"10.1128","volume":"71","author":[{"given":"Suresh G.","family":"Joshi","sequence":"first","affiliation":[{"name":"Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles W.","family":"Francis","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev K.","family":"Sahni","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 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