Cellular and molecular mechanisms of T lymphocytes apoptosis by Actinobacillus actinomycetemcomitans
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- Tez No: 401298
- Danışmanlar: DR. HOMAYOUN H. ZADEH
- Tez Türü: Doktora
- Konular: Biyoloji, Genetik, Moleküler Tıp, Biology, Genetics, Molecular Medicine
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2003
- Dil: İngilizce
- Üniversite: University of Southern California
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Moleküler Biyoloji ve Genetik Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 132
Özet
Özet yok.
Özet (Çeviri)
Actinobacillus actinomycetemcomitans is a major pathogen implicated in several forms of periodontal diseasesj as well as nonoral infections. Despite extensive investigation, the exact mechanism of pathogenicity of this microorganism remains unknown. There is evidence that this bacterium uses a number of i mechanisms to suppress the host response. One such mechanisms is the killing of '' "tltl host cells by apoptosis. The cytotoxicity of A. actinomycetemcomitans toward a number of cell types has been demonstrated, however comparatively little information is available on A. actinomycetemcomitans -induced apoptosis of T cells. Therefore, the aim of the present study was to determine the magnitude and mechanism of T cell apoptosis in response to A. actinomycetemcomitans. To that end, an in vitro culture system was used, where peripheral blood mononuclear i cells (PBMC) were cultured at different time points in the presence of different preparations of A. actinomycetemcomitans. Cells were immunofluorescently labeled with monoclonal antibodies or reagents specific for markers associated with apoptosis, in concert with lineage and subset-specific markers. Flow cytometric analysis was then performed to determine the proportion of cells with a specific marker. Results demonstrated that following exposure of T cells to preparations of A. actinomycetemcomitans, progressively, plasma membrane alterations associated with apoptosis were detected. These included extemalization of phosphatidylserine, which was detected in approximately half of all T cells by 96 hours. This was followed by loss of membrane integrity. The data presented here provides evidence for the induction of apoptosis among the majority of the T cells responding to A. actinomycetemcomitans. To investigate the mechanism(s) of A. actinomycetemcomitans induced T cell apoptosis, the involvement of the Fas-mediated apoptotic pathway was investigated. Results demonstrated upregulation of Fas and activation of caspase- 3 in T cells in response to A. actinomycetemcomitans. Monocytes were the only cells analyzed to constitutively express FasL, which was further upregulated in response to A. actinomycetemcomitans, while T cells expressed FasL only after this stimulation. Depletion of monocytes prior to stimulation with A. actinomycetemcomitans led to a marked decline in apoptosis. Blocking Fas-FasL interactions lead to a significant decline, but not abolition of T cell apoptosis. Nearly all T cells expressed Bcl-2 at the outset of culture and Bcl-2 expression declined in T cells stimulated with A. actinomycetemcomitans. Collectively, these data provide evidence for the induction of T cell apoptosis by A. actinomycetemcomitans via Fas-mediated pathway. A. actinomycetemcomitans expresses two known cytotoxin, namely leukotoxin (Ltx) and cytolefhal distending toxin (CDT). CDT is also capable of inducing a cell cycle arrest in T cells in the G2 phase. However the extent of contribution of each of these toxins, as well as the existence of other possible molecules with cytolytic and cytostatic activities is not known. To that end, a series of isogenic deletion mutants were generated. The cytolytic and cytostatic activities of wild type and isogenic deletion mutants were compared. Results showed that the leukotoxin and CDT partially contributed to the cytotoxicity of A. actinomycetemcomitans, since each of the isogenic mutants exhibited reduced apoptosis for T cells. The expression of Itx and each of the cdt gene loci partially contributed to the cytotoxicity of A. actinomycetemcomitans, since each of the isogenic mutants exhibited reduced cytotoxicity for T cells. On the other hand, the ability to induce a cell cycle block was abolished in each of the cdt isogenic mutants. Double mutants with deletion of Itx, as well as all 3 cdt gend loci retained significant ability to induce T cell apoptosis. Collectively, these data provide evidence for the expression of other cytolytic molecule(s) of A. actinomycetemcomitans distinct from CDT and leukotoxin, while suggesting that the cytostatic function is dependent on the expression of all 3 cdt gene loci.
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