| Project/Area Number |
18590398
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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 |
Parasitology (including Sanitary zoology)
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| Research Institution | Gunma University |
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Principal Investigator |
SHIMADA Junko Gunma University, School of Medicine, Professor (20211964)
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| Co-Investigator(Kenkyū-buntansha) |
HATABU Toshimitsu Gunma University, School of Medicine, Assistant professor (60344917)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,990,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | PATHOGEN / INFECTION / PROTOZOAN PARASITES / APOPTOSIS / Trypanosoma cruzi / アポトーシス抑制 |
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| Research Abstract |
Trypanosoma cruzi is a protozoan parasite that causes Chagas' disease in South America. We demonstrated that the parasite infection inhibits death receptor-mediated apoptosis in host cells. This inhibition is thought to be a defense strategy for the parasite to escape from host immune responses. We clarified that the parasite dramatically up-regulates cellular FLICE-like inhibitory protein (c-FLIP), the only known mammalian inhibitor specific for death receptor signaling. We also found that c-FLIP knock-down with a small interfering RNA significantly restores Fas-mediated apoptosis in infected cells. To elucidate the mechanisms of c-FLIP up-regulation, we examined posttranscriptional regulation of c-FLIP expression in T. cruzi infected cells. It has been reported that c-FLIP is a key target for S-nitrosylation by nitric oxide (NO) in cancer cells. HT1080 or THP-1 cells were infected with T. cruzi or treated with NO donors, and further cultured for 1-3 days. Cell lysates were immunoprecipitated and analyzed by Western blot using anti-S-nitrosocysteine antibody in control and infected cells. By the addition of the NO donors, sodium nitroprusside, the nitrosylated level of FLIP was strongly increased. In infected cells nitrosylated c-FLIP was clearly detected in supernatant. These findings suggest that endogenously produced NO synthesized by NO synthase is a mediator of T. cruzi infection. S-nitrosylation of FLIP is an important mechanism utilized by NO rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL.
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