2003 年度実績報告書

単純ヘルペスウイルスによるアポトーシスの誘導・抑制の分子機構

研究課題

研究課題/領域番号	14370100
研究機関	名古屋大学
研究代表者	西山幸廣名古屋大学, 大学院・医学系研究科, 教授 (60115615)
キーワード	アポトーシス / US3遺伝子 / UL14遺伝子 / 単純ヘルペスウイルス
研究概要	ウイルス感染に伴う細胞死は受身的、消耗的なものというよりむしろ宿主防御反応に関わる積極的な役割を持つ。一方、ウイルスはこのような細胞死(アポトーシス)を回避する、あるいは抑制するための様々な機構を獲得している。本研究では、単純ヘルペスウイルス(HSV)によるアポトーシスの誘導因子を同定するとともに、誘導と抑制の子機構を解明しようとするものである。 UL14遺伝子産物は我々が初めて同定し、その性状について明らかにしてきたが、UL14蛋白質の機能についてさらに明らかにするため、UL14発現細胞(14/HEp-2)の性状について非発現細胞と比較検討した。その結果、14/HEp-2はHEp-2に比べて、様々なアポトーシスの誘導刺激に対して抵抗性になっていることが判明した。これはcaspas-3活性化やPARPの切断によっても確認された。UL14欠損HSVと野生株との比較から、感染細胞においてもUL14がanti-apoptoticに作用している可能性が示唆された。US3遺伝子産物はセリン/スレオニンプロテインキナーゼ(PK)でアポトーシス抑制作用をもつことを明らかにしてきた。中枢神経系のHSV感染におけるUS3の役割を知るために脳定位固定装置を用いたマイクロインジェクション法によりマウス嗅球へUS3欠損ウイルス(L1BR1)を接種し、野生株、US3レスキュー株と比較検討した。嗅覚皮質の神経細胞はいずれの感染でもウイルス抗原陽性となったが、L1BR1感染細抱においてのみ核内が抗phospho-JNK (Thr184/Thr185)抗体、抗phospho-c-Jun (Ser63)抗体で陽性に染色された。TUNEL法では、L1BR1感染で最も高頻度に陽性(約92%)となったが、野生株や復帰株でも56〜65%の陽性率を示した。以上の観察から、HSV感染による中枢神経細胞のアポトーシスの抑制にもUS3が関与していることが示唆された。我々はウイルス粒子蛋白質のある種のものがアポトーシス誘導因子になりうることを明らかにしてきた。しかし、アポトーシス誘導粒子蛋白質の同定はまだ成功していない。

研究成果

(29件)

すべてその他

すべて文献書誌 (29件)

[文献書誌] Sugiura, S., Yoshikawa, T., Nishiyama, Y., et al.: "Detection of human cytomegalovirus DNA in perilymph of patients with sensorineural hearing loss using real-time PCR."J Med Virol. 69. 72-75 (2003)
[文献書誌] Kudo, A., Fuiita, M., Kiyono, T., et al.: "Reactivation of lytic replication from Epstein-Barr virus latently infected B-cells occurs with high S-phase CDK activity while inhibiting cellular DNA replication."J Virol. 77. 851-861 (2003)
[文献書誌] Kawaguchi, Y., Kato, K., Tanaka, M., et al.: "Conserved protein kinases encoded by herpesviruses and a cellular protein kinase cdc2 target the same phosphorylation site in eukaryotic elongation factor 1δ."J Virol. 77. 2359-2368 (2003)
[文献書誌] Nozawa, N., Daikoku, T., Koshizuka, T., et al.: "Subcellular localization of UL51 protein of herpes simplex virus type 1 and role of palmitoylation in Golgi targeting."J Virol. 77. 3204-3216 (2003)
[文献書誌] Takakuwa, T., Goshima, F., Nozawa, N., et al.: "Oncolytic viral therapy for peritoneally disseminated tumor using a spontaneously generated herpes simplex virus type 1 variant in immunocompetent mice."Arch Virol. 148. 813-825 (2003)
[文献書誌] Kimata, H., Takakuwa, H., Goshima, F., et al.: "Effective treatment of disseminated peritoneal colon cancer with new replication-competent heroes simplex virus."Hepato-Gastroenterogy. 50. 961-966 (2003)
[文献書誌] Yoshikawa, T., Akimoto, S., Nishimura, N., et al.: "Evaluation of active human herpesvirus 6 infection by reverse transcription-PCR."J Med Virol. 70. 267-272 (2003)
[文献書誌] Yoshikawa, T., Yoshida, J., Hamaguchi, M., et al.: "Human herpesvirus 7-associated meningitis and optic neuritis in a patient after allogeneic stem cell transplantation."J Med Virol. 70. 440-443 (2003)
[文献書誌] Yoshikawa, T., Goshima, F., Akimoto, S., et al.: "Human herpesvirus 6 infection of human epidermal cell line : pathogenesis of skin manifestations."J Med Virol. 71. 62-68 (2003)
[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "Differential activation of JNK/SAPK and p38 MAPK signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus."J Gen Virol. 84. 2401-2408 (2003)
[文献書誌] Nawa, A., Nozawa, N., Goshima, F., et al.: "Oncolytic viral therapy for human ovarian cancer using a novel replication competent herpes simplex virus type 1 mutant in a mouse model."Gynecol Oncol. 91. 81-88 (2003)
[文献書誌] Kato, K., Yokoyama, A., Tohya, Y., et al.: "Identification of protein kinases responsible for phosphorylation of Epstein-Barr virus nuclear leader protein at serine 35 that regulates its coactivator function."J Gen Virol. 84. 3381-3392 (2003)
[文献書誌] Yamauchi, Y., Daikoku, T., Goshima, R, et al.: "Herpes simplex virus UL14 protein blocks apoptosis."Micribiol Immunol. 47. 685-689 (2003)
[文献書誌] Kimura, H., Ito, Y., Futamura, M., Ando, Y., et al.: "Relapse of neonatal herpes simplex virus infection."Arch Dis Child. 88. 483-486 (2003)
[文献書誌] Ihira, M., Yoshikawa, T., Ohashi, M., et al.: "Variation of human herpesvirus 7 shedding in saliva."J Infect Dis. 188. 1352-1354 (2003)
[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "The US3 protein kinase of herpes simplx virus attenuates the activation of the JNK signal transduction pathway in infected piriform cortex neurons in C57BL/6 mice."Neurosci Lett. 351. 201-205 (2003)
[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "Iba 1-expressing microglia-like cells respond to herpes simplex virus infection in the mouse trigeminal ganglion."Mol Brain Res. 120. 52-56 (2003)
[文献書誌] Kudoh, A., Daikoku, T., Sugaya, Y., et al.: "Inhibition of S-phase cyclin-dependent kinase activity blocks expression of Epstein Barr virus immediate early and early genes, preventing viral lytic replication."J Virol. 78. 104-115 (2004)
[文献書誌] Nishiyama, Y.: "Herpes simplex virus gene products : the accessories reflect her lifestyle well."Rev Med Virol. 14. 33-46 (2004)
[文献書誌] Mori, L, Yokochi, T., Koide, N., et al.: "PCR search for HSV-1 genome in the brain section of patients with familal Alzheimer's disease."J Clin Microbiol. 42. 936-937 (2004)
[文献書誌] Tesnigahara, O., Goshima, F., Takao, K., et al.: "Oncolytic viral therapy for breast cancer with herpes simplex virus type 1 mutant HF10."J Surg Oncol. 85. 42-47 (2004)
[文献書誌] Ihira M, Yoshikawa T, Enomoto Y, et al.: "Rapid diagnosis of human herpesvirus 6 infection by a novel DNA amplification method, Loop-mediated isothermal amplification."J Clin Microbiol. 42. 140-145 (2004)
[文献書誌] Sugiura, S., Goshima, F., Takakuwa, H., et al.: "Treatment of solid sarcomas in immunocometent mice with novel oncolytic herpes simplex viruses."Otolaryngol Head Neck Surg. (in press). (2004)
[文献書誌] Kanamori, M., Watanabe, S., Honma, R., et al.: "Epstein-Barr virus nuclear antigen leader protein induces expression of thymus and activation-regulated chemokine in B cells."J Virol. (in press). (2004)
[文献書誌] Niimi, A., Limsirichaikul, S., Yoshoda, S., et al.: "Palm residue mutant in DNA polymerases α and η alter DNA replication fidelity and translesion activity."Mol Cell Biol. (in press). (2004)
[文献書誌] Mori, I., Kimura, Y., Naiki, H., et al.: "Limited reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease."J Med Virol. (in press). (2004)
[文献書誌] Mori, I., Nishiyama, Y., Yokochi, T., Kimura, Y.: "Virus-induced neuronal apoptosis as pathological and protective responses of the host."Rev Med Virol. (in press). (2004)
[文献書誌] Nishimura, H., Yajima, T., Kagimoto, Y., et al.: "Intraepithelial γδ T may bridge a gap between innate and acquired immunity to herpes simplex virus type 2."J Virol. (in press). (2004)
[文献書誌] Nakao, A., Kimata, H., Imai, T., et al.: "Intratumoral injection of herpes simplex HF10 in rexurrent breast cancer."Ann Oncol. (in press). (2004)

2003 年度 実績報告書

単純ヘルペスウイルスによるアポトーシスの誘導・抑制の分子機構

研究代表者

西山 幸廣 名古屋大学, 大学院・医学系研究科, 教授 (60115615)

研究成果

[文献書誌] Sugiura, S., Yoshikawa, T., Nishiyama, Y., et al.: "Detection of human cytomegalovirus DNA in perilymph of patients with sensorineural hearing loss using real-time PCR."J Med Virol. 69. 72-75 (2003)

[文献書誌] Kudo, A., Fuiita, M., Kiyono, T., et al.: "Reactivation of lytic replication from Epstein-Barr virus latently infected B-cells occurs with high S-phase CDK activity while inhibiting cellular DNA replication."J Virol. 77. 851-861 (2003)

[文献書誌] Kawaguchi, Y., Kato, K., Tanaka, M., et al.: "Conserved protein kinases encoded by herpesviruses and a cellular protein kinase cdc2 target the same phosphorylation site in eukaryotic elongation factor 1δ."J Virol. 77. 2359-2368 (2003)

[文献書誌] Nozawa, N., Daikoku, T., Koshizuka, T., et al.: "Subcellular localization of UL51 protein of herpes simplex virus type 1 and role of palmitoylation in Golgi targeting."J Virol. 77. 3204-3216 (2003)

[文献書誌] Takakuwa, T., Goshima, F., Nozawa, N., et al.: "Oncolytic viral therapy for peritoneally disseminated tumor using a spontaneously generated herpes simplex virus type 1 variant in immunocompetent mice."Arch Virol. 148. 813-825 (2003)

[文献書誌] Kimata, H., Takakuwa, H., Goshima, F., et al.: "Effective treatment of disseminated peritoneal colon cancer with new replication-competent heroes simplex virus."Hepato-Gastroenterogy. 50. 961-966 (2003)

[文献書誌] Yoshikawa, T., Akimoto, S., Nishimura, N., et al.: "Evaluation of active human herpesvirus 6 infection by reverse transcription-PCR."J Med Virol. 70. 267-272 (2003)

[文献書誌] Yoshikawa, T., Yoshida, J., Hamaguchi, M., et al.: "Human herpesvirus 7-associated meningitis and optic neuritis in a patient after allogeneic stem cell transplantation."J Med Virol. 70. 440-443 (2003)

[文献書誌] Yoshikawa, T., Goshima, F., Akimoto, S., et al.: "Human herpesvirus 6 infection of human epidermal cell line : pathogenesis of skin manifestations."J Med Virol. 71. 62-68 (2003)

[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "Differential activation of JNK/SAPK and p38 MAPK signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus."J Gen Virol. 84. 2401-2408 (2003)

[文献書誌] Nawa, A., Nozawa, N., Goshima, F., et al.: "Oncolytic viral therapy for human ovarian cancer using a novel replication competent herpes simplex virus type 1 mutant in a mouse model."Gynecol Oncol. 91. 81-88 (2003)

[文献書誌] Kato, K., Yokoyama, A., Tohya, Y., et al.: "Identification of protein kinases responsible for phosphorylation of Epstein-Barr virus nuclear leader protein at serine 35 that regulates its coactivator function."J Gen Virol. 84. 3381-3392 (2003)

[文献書誌] Yamauchi, Y., Daikoku, T., Goshima, R, et al.: "Herpes simplex virus UL14 protein blocks apoptosis."Micribiol Immunol. 47. 685-689 (2003)

[文献書誌] Kimura, H., Ito, Y., Futamura, M., Ando, Y., et al.: "Relapse of neonatal herpes simplex virus infection."Arch Dis Child. 88. 483-486 (2003)

[文献書誌] Ihira, M., Yoshikawa, T., Ohashi, M., et al.: "Variation of human herpesvirus 7 shedding in saliva."J Infect Dis. 188. 1352-1354 (2003)

[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "The US3 protein kinase of herpes simplx virus attenuates the activation of the JNK signal transduction pathway in infected piriform cortex neurons in C57BL/6 mice."Neurosci Lett. 351. 201-205 (2003)

[文献書誌] Mori, I., Goshima, F., Koshizuka, T., et al.: "Iba 1-expressing microglia-like cells respond to herpes simplex virus infection in the mouse trigeminal ganglion."Mol Brain Res. 120. 52-56 (2003)

[文献書誌] Kudoh, A., Daikoku, T., Sugaya, Y., et al.: "Inhibition of S-phase cyclin-dependent kinase activity blocks expression of Epstein Barr virus immediate early and early genes, preventing viral lytic replication."J Virol. 78. 104-115 (2004)

[文献書誌] Nishiyama, Y.: "Herpes simplex virus gene products : the accessories reflect her lifestyle well."Rev Med Virol. 14. 33-46 (2004)

[文献書誌] Mori, L, Yokochi, T., Koide, N., et al.: "PCR search for HSV-1 genome in the brain section of patients with familal Alzheimer's disease."J Clin Microbiol. 42. 936-937 (2004)

[文献書誌] Tesnigahara, O., Goshima, F., Takao, K., et al.: "Oncolytic viral therapy for breast cancer with herpes simplex virus type 1 mutant HF10."J Surg Oncol. 85. 42-47 (2004)

[文献書誌] Ihira M, Yoshikawa T, Enomoto Y, et al.: "Rapid diagnosis of human herpesvirus 6 infection by a novel DNA amplification method, Loop-mediated isothermal amplification."J Clin Microbiol. 42. 140-145 (2004)

[文献書誌] Sugiura, S., Goshima, F., Takakuwa, H., et al.: "Treatment of solid sarcomas in immunocometent mice with novel oncolytic herpes simplex viruses."Otolaryngol Head Neck Surg. (in press). (2004)

[文献書誌] Kanamori, M., Watanabe, S., Honma, R., et al.: "Epstein-Barr virus nuclear antigen leader protein induces expression of thymus and activation-regulated chemokine in B cells."J Virol. (in press). (2004)

[文献書誌] Niimi, A., Limsirichaikul, S., Yoshoda, S., et al.: "Palm residue mutant in DNA polymerases α and η alter DNA replication fidelity and translesion activity."Mol Cell Biol. (in press). (2004)

[文献書誌] Mori, I., Kimura, Y., Naiki, H., et al.: "Limited reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease."J Med Virol. (in press). (2004)

[文献書誌] Mori, I., Nishiyama, Y., Yokochi, T., Kimura, Y.: "Virus-induced neuronal apoptosis as pathological and protective responses of the host."Rev Med Virol. (in press). (2004)

[文献書誌] Nishimura, H., Yajima, T., Kagimoto, Y., et al.: "Intraepithelial γδ T may bridge a gap between innate and acquired immunity to herpes simplex virus type 2."J Virol. (in press). (2004)

[文献書誌] Nakao, A., Kimata, H., Imai, T., et al.: "Intratumoral injection of herpes simplex HF10 in rexurrent breast cancer."Ann Oncol. (in press). (2004)

2003 年度実績報告書

西山幸廣名古屋大学, 大学院・医学系研究科, 教授 (60115615)