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フリーラジカルによるウイルス遺伝子変異メカニズムの解明

Research Project

Project/Area Number 10877054
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Virology
Research InstitutionKumamoto University

Principal Investigator

赤池 孝章  熊本大学, 医学部, 助教授 (20231798)

Co-Investigator(Kenkyū-buntansha) 加藤 篤  東京大学, 医科学研究所, 助手 (40152699)
前田 浩  熊本大学, 医学部, 教授 (90004613)
宮本 洋一  熊本大学, 医学部, 助手 (20295132)
豊田 哲也  久留米大学, 医学部, 教授 (00197972)
永井 美之  東京大学, 医科学研究所, 教授 (20022874)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsフリーラジカル / NO / パーオキシナイトライト / 遺伝子変異 / ウイルス感染病態 / ウイルス分子進化
Research Abstract

ウイルス感染病態において誘導型NO合成酵素(inducible NO synthase,iNOS)から過剰に産生されるNOは、共存する分子状酸素(O_2)や酸素ラジカル(活性酸素)などと反応し、パーオキシナイトライト(ONOO^-)などの反応性窒素酸化物の生成を介して、宿主に酸化ストレスをもたらす。一方で、感染炎症における酸化ストレスは、生体内で増殖するウイルスそのものにも加えられることが予想される。RNAウイルスは、一回の複製でヌクレチド残基あたり10^<-5>〜10^<-3>という頻度で変異し、極めて高度な遺伝的多様性を有しており、様々な環境中のストレスにより淘汰されながら分子進化を繰り返している。この様なウイルスの多様性は、これまで主にRNA複製の不正確さにより説明されてきたが、その分子メカニズムは今だに不明である。そこで今回、NOよりもたらされる酸化ストレスのウイルスの分子進化への関わりについて検討した。このため、変異のマーカー遺伝子としてgreen fluorescent protein(GFP)を組み込んだセンダイウイルス(GFP-SeV)を用いてNOやパーオキシナイトライトによるウイルス遺伝子変異促進作用について解析した。その結果、in vitroの系において、パーオキシナイトライトはウイルスに対して非常に強い変異原性を示した。さらにiNOS欠損マウスおよび野生マウスのGFP-SeV感染系において、野生マウスではiNOS欠損マウスの7倍程度高いウイルス遺伝子変異率が認められた。これらの知見は、ウイルス感染・炎症反応にともない過剰に産生されるNOやパーオキシナイトライトが、ウイルスの変異速度を高め、その分子進化に関与していることを示唆している。

Report

(2 results)
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] T. Sawa,et al.: "Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds : Implications for the anti promoter effect of vegetables"J. Agric. Food Chem.. 42. 397-402 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S. Fujii,et al.: "Role of mitrec oxide in pathogenesis o herpes simplex virus encephalitis in rats"Virology. 256. 203-212 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H. Sugiura. et al.: "Role of peroxynitrite in airway microvascular hyperpermeability during late allergic phase in guinea pigs"Am. J. Respir. Crit. Care Med.. 160. 663-671 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Doi,et al.: "Induction of haem oxygenase-1 by nitric oxide and eschemia in experimental solid tumors and implecations for tumour growth"Br. J. Cancer. 80. 1945-1954 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Inoune,et al.: "Nitorsothiol formation catalyzed by ceruloplasmin : Implication for cytoprotective mechanism in vivo"J. Biol. Chem.. 274. 27069-27075 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y. Suzuki,et al.: "Direct evidence of in vivo nitric oxide production and inducible nitric oxide synthase mRNA expression in the brain of living rat experimental meningitis"J. Cereb. Blood Flow Metab.. 19. 1175-1178 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y. Miyamoto,et al.: "Novel functions of human α_1-protease inhibitor after S-nitorsylation : Inhibition of cysteine protease and antibacterial activity"Biochem. Biophys. Res. Commun.. 267. 918-923 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y. Miyamoto,et al.: "S-Nitrosylated human α_1-protease inhibitor"Biochem. Biophys.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Akaike,et al.: "Viral mutation accelerated by nitric oxide production during infection in vivo"FASEB J.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Akaike and H. Maeda: "Nitric Oxide and Infection (ed. F. C. Fang)"Kluwer Academic/Plenum Publishing Co., New York. 19 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Akaike: "Guanidino Compounds (eds. M. Mori, M. Ishida and J. F. Clark)"Blackwell Science Asia, Tokyo. 5 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Akaike and H. Maeda: "Nitric Oxide (ed. L. J. Ignarro)"Academic Press, San Diego (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akaike,T.,et al.: "Free radicals in viral pathogenesis:Molecular mechanisms involving superoxide and NO" Proc.Soc.Exp.Biol.Med.217. 64-73 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshida,M.,et al: "Effect of the NO scavenger carboxy-PTIO on endothelium-dependent vasorelaxation of various blood vessels from rabbits" Life Sciences. 62. 203-211 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] WuJ.,et al.: "Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor,and a nitric oxide scavenger" Cancer Res.58. 159-165 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maeda,H.,et al.: "Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals" Biol.Chem.379. 193-200 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sato,K.,et al.: "Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice" Am.J.Respir.Crit.Care Med.157. 853-857 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maeda,H.,and Akaike,T.: "Nitric oxide and oxygen radicals in infection,inflammation,and cancer" Biochemistry(Moscow). 63. 854-865 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshida,M.,et al.: "The possible effect of nitric oxide on relaxation and noradrenaline release in the isolated rabbit urethra" Eur.J.Pharmacol.357. 213-219 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakatsubo,N.,et al.: "Improved nitric oxide detection using 2,3-diaminonaphthalene and its application to the evaluation of novel nitric oxide synthase inhibitors" Biol.Pharm.Bull.21. 1247-1250 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sawa,T.,et al.: "Lipid peroxyl radicals from oxidized oils and heme-iron:Implication of a high-fat diet in colon carcinogenesis" Cancer Res. Epidemiol.Biomarkers & Prevention. 7. 1007-1012 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Doi,K.,et al.: "Induction of heme oxygenase-1 by nitric oxide and ischemia in experimental solid tumors and implications for tumorgrowth" Br.J.Cancer. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujii,S.,et al.: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats" Virology. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maeda,H.,et al.: "Free radical generation from heterocyclic amines by cytochromes b_5 reductase in the resence of NADH" Cancer Letters. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maeda,H.,et al.: "Kallikrein-kinin in infection and cancer" Immunopharmacology. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Akaike,T.,and Maeda,H.: "Nitric oxide and oxygen radicals in infection,inflammation,and cancer Oxide and Infection(ed.F.C.Fang)" Plenum Publishing co.,New York(in press), (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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