Short and long term influences of Chlamydia lgrehmtrlni infection on host cell cycle, apoptosis and senescence programs
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Beschreibung
Chlamydia are obligate intracellular bacteria, which can survive in their host cells for years in a state of persistency. In acute infections, Chlamydia are known to suppress apoptosis programs of the host cell. Additionally, they can influence the cell cycle of the host cells and increase chromosomal instability of infected host cells even after the infection has been cleared by antibiotics. Chlamydial infections have been statistically correlated with the development of cancer.
In the present study the influence of chlamydial infections on cell cycle, DNA damage, apoptosis and senescence pathways of the host cells is examined in long term as well as in acute infections. In contrast to other studies of chlamydial infection, here a more primary cell line (IMR90E1A) was used to better assess the changes, which are induced by the infection in yet untransformed cells. IMR90E1A cells are embryonic fibroblast cells, which stably express the viral oncogene E1A. E1A increases the proliferative capacity of IMR90 cells, but at the same time enhances their susceptibility towards apoptosis. Additionally, E1A does not fully immortalize human primary IMR90 cells, which are still capable of undergoing replicative senescence.
Cell cycle, DNA damage, apoptosis and senescence pathways are highly interconnected and mutually influence each other in multiple ways. In this study, changes of expression and activity of three major components of these signaling pathways as well as the consequences of these changes in acute and long term chlamydial infection are depicted. The factors, which were examined, are: the regulator of cell cycle stop, senescence and apoptosis p53, the cell cycle stop and senescence inducer p21 and the apoptosis and senescence inhibitor hTERT. The data presented demonstrate that acute chlamydial infection leads to a profound upregulation of hTERT expression and activity. At the same time p53 activity is drastically reduced without affecting p53 protein level.
In long term chlamydial infections, the baseline activity of p53 in infected and non infected cells is similar, but the activation of p53 by the DNA damage inducer Etoposide is still inhibited in infected cells. Also in long term infections, p21 expression is drastically reduced. This downregulation of p21 was observed till 18 days post infection. Later time points were not investigated. At 18 days post infection, and after several population doublings of the host cells, Chlamydia are not detectable in the cell culture anymore. The change of p21 gene expression in cells derived from the formerly infected cell pool, however still persists. Therefore the potential involvement of epigenetic mechanisms in host cell gene regulation by Chlamydia was investigated.
P21 downregulation additionally was found to be correlated to reduced p53 binding to the p21 promoter in long term infections and long term infected cells displayed a faster cell division rate than non-infected cells.
Based on this data it is evident, that Chlamydia are able to significantly alter and maybe permanently disrupt host cell senescence and cell cycle pathways. This changes induced by Chlamydia may well lead to malignant transformation and the development of cancer in infected host cells.
Chlamydia are obligate intracellular bacteria, which can survive in their host cells for years in a state of persistency. In acute infections, Chlamydia are known to suppress apoptosis programs of the host cell. Additionally, they can influence the cell cycle of the host cells and increase chromosomal instability of infected host cells even after the infection has been cleared by antibiotics. Chlamydial infections have been statistically correlated with the development of cancer.
In the present study the influence of chlamydial infections on cell cycle, DNA damage, apoptosis and senescence pathways of the host cells is examined in long term as well as in acute infections. In contrast to other studies of chlamydial infection, here a more primary cell line (IMR90E1A) was used to better assess the changes, which are induced by the infection in yet untransformed cells. IMR90E1A cells are embryonic fibroblast cells, which stably express the viral oncogene E1A. E1A increases the proliferative capacity of IMR90 cells, but at the same time enhances their susceptibility towards apoptosis. Additionally, E1A does not fully immortalize human primary IMR90 cells, which are still capable of undergoing replicative senescence.
Cell cycle, DNA damage, apoptosis and senescence pathways are highly interconnected and mutually influence each other in multiple ways. In this study, changes of expression and activity of three major components of these signaling pathways as well as the consequences of these changes in acute and long term chlamydial infection are depicted. The factors, which were examined, are: the regulator of cell cycle stop, senescence and apoptosis p53, the cell cycle stop and senescence inducer p21 and the apoptosis and senescence inhibitor hTERT. The data presented demonstrate that acute chlamydial infection leads to a profound upregulation of hTERT expression and activity. At the same time p53 activity is drastically reduced without affecting p53 protein level.
In long term chlamydial infections, the baseline activity of p53 in infected and non infected cells is similar, but the activation of p53 by the DNA damage inducer Etoposide is still inhibited in infected cells. Also in long term infections, p21 expression is drastically reduced. This downregulation of p21 was observed till 18 days post infection. Later time points were not investigated. At 18 days post infection, and after several population doublings of the host cells, Chlamydia are not detectable in the cell culture anymore. The change of p21 gene expression in cells derived from the formerly infected cell pool, however still persists. Therefore the potential involvement of epigenetic mechanisms in host cell gene regulation by Chlamydia was investigated.
P21 downregulation additionally was found to be correlated to reduced p53 binding to the p21 promoter in long term infections and long term infected cells displayed a faster cell division rate than non-infected cells.
Based on this data it is evident, that Chlamydia are able to significantly alter and maybe permanently disrupt host cell senescence and cell cycle pathways. This changes induced by Chlamydia may well lead to malignant transformation and the development of cancer in infected host cells.
Autor*in
Inken Padberg