| Project/Area Number |
17590391
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bacteriology (including Mycology)
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| Research Institution | Hokkaido University (2006)
Osaka University (2005) |
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Principal Investigator |
YAMAGUCHI Hiroyuki Hokkaido University, school of Medicine, Professor, 医学部, 教授 (40221650)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Yoshimasa Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20010100)
KAWANO Sunao Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60133138)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Chlamydia pneumoniae / lymphocyte / atherosclerosis / persistent infection / CD3 / CD25 / phenoxazine / NOD mouse / リンパ球 / プロスタグランジンE_2 / IL-2レセプター / Cox-2 |
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| Research Abstract |
Current studies have revealed that the obligate intracellular bacterium Chlamydia (Chlamydophila) pneumoniae is associated not only with respiratory diseases, but also with chronic diseases such as atherosclerosis. The detection of the C. pneumoniae DNA or antigen in coronary atherosclerotic plaque and peripheral blood of the patients with cardiovascular diseases has strengthened the likelihood of its possible involvement in the pathogenesis of atherosclerosis. Moreover, several studies indicate that viable C. pneumoniae can be detected in atherosclerotic plaques from patients of advanced age with coronary heart disease by both culture and RT-PCR methods. Our recent studies also showed that viable C. pneumoniae are readily detectable in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, indicating that the presence of viable bacteria in the blood stream might be a risk factor for the development of atherosclerosis. C. pneumoniae preferentially infects respiratory
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tract epithelial cells as well as macrophages. On the other hand, our previous studies revealed that lymphocyte is another host cell permitting C. pneumoniae infection with a persistent nature. Since lymphocytes are a major immune cell type besides macrophages in the development of atherosclerosis, interaction between lymphocytes and this pathogen may contribute to the pathogenesis of chronic inflammatory diseases associated with C. pneumoniae. We first attempted to assess a possible association between development of diabetes in non-obese diabetic (NOD) mice and dissemination of C. pneumoniae from lung to peripheral blood. By real-time reverse transcription-polymerase chain reaction (RT-PCR) with primers for C. pneumoniae 16S rRNA, following multiple intranasal inoculations,. bacteria in lung were detected in NOD mice with diabetes (38.5 %) as well as ICR mice (40 %), but prevalence of bacteria in NOD mice without diabetes (Pre-diabetic NOD mice and non-diabetic retired NOD mice) was very low (4.8 %).The bacteria were only detected in peripheral blood mononuclear cells (PBMCs) cultured withhydrocortisone of the NOD mice with diabetes (53.8 %). Results of immunostaining with fluorescein isothiocyanate-conjugated anti-chlamydia monoclonal antibody also showed the presence of bacterial antigens m the lungs and the PBMCs judged as positive by the RT-PCR. The results clearly showed that the development of diabetes in NOD mouse appears to be one of critical factors for promoting the dissemination of C. pneumoniae from lung to peripheral blood. Second, we examined a possible alteration of CD3 and CD25 expressions of human lymphocytes [Molt-4 cells and enriched lymphocytes from peripheral blood mononuclear cells (PBMCs)] by C. pneumoniae infection. The expression levels of both molecules of Molt-4 cells were significantly decreased by C. pneumoniae infection. C. pneumoniae clinical isolates also caused the alteration of both expressions of the infected cells. In contrast, C. trachomatis did not cause any alteration of both expressions of Molt-4 cells. Heat-killed bacteria and HEp-2 lysate as mock did not cause any alteration of CD3 expression of lymphocytes. Addition of either NS-398 (Cox-2 inhibitor) or AH-23848 (EP4 prostanoid receptorantagonist) tothe culture abolishedthe alteration of CD3 expression ofthe infected cells. The enhanced prostaglandin E_2 (PGE_2) productions in the culture supernatant of infected cells were also confirmed by competitiveELISA. C. pneumoniae infection of enriched lymphocytesfromPBMCs also causedanalteration of CD3 expression.Thus, C. pneumoniae infection of human lymphocytes induces an alteration of CD3 expression mediated by PGE_2 production. Since CD3 molecule has a major role in the signal transduction following antigen recognitions, such alteration may be involved in C.pneumoniae persistent infection of lymphocytes. Also, we foundthat 2-amino-phenoxazine 3-one (phenoxazine derivate: Phx-3)inhibits C. pneumoniae replication in human monocytic cells as well as epithelial cells, partially depending on the tryptophan-metabolic pathway of host cells. Less
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