Establishment of Model Mice of Rheumatoid Arthritis by using nonstructural protein 1 (NS1) of parvovirus B19

• Project/Area Number: 10470074
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Tohoku University
• Principal Investigator: SUGAMURA Kazuo Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (20117360)
• Co-Investigator(Kenkyū-buntansha): ASAO Hironobu Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (80250744) ; ISHII Naoto Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (60291267) ; 田中 伸幸 東北大学, 医学部, 助手 (60280872)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥12,800,000 (Direct Cost: ¥12,800,000); Fiscal Year 1999: ¥6,100,000 (Direct Cost: ¥6,100,000); Fiscal Year 1998: ¥6,700,000 (Direct Cost: ¥6,700,000)
• Keywords: parvovirus / rheumatoid arthritis / apoptosis / hydrops fetalis / ヒト・パルボウイルス / 転写活性化因子 / 慢性関節リウマチ / 伝染性紅斑 / 非免疫性胎児水腫

Research Abstract

Human parvovirus B19 (B19) infection causes a wide variety of human diseases including erythema infectiosum, aplastic crises and nonimmune hydrops fetalis (NIHF). Epidemiological studies of B19 virus has suggested a possible relationship between B19 infection and rheumatoid arthritis (RA). Since B19 virus produces one major nonstructural protein, NS1, which is known to harbor functions of apoptotic cytotoxicity and transcriptional activator, we suspect that NS1 plays an important role in the occurrence of infectious diseases caused by B19 virus. In this research project, we attempted to generate NS1 transgenic mice, which develop NHIF and RA. We first generated transgenic mice of NS1, of which expression is controlled by the GATA1-promoter. A line of NS1-Tg mice showed embryonic lethality within E6.5, and two other lines were also embryonically lethal between E14.5 and E15.5 with severe anemias. These phenotypes of NS1-Tg mice resemble those of human NIHF, suggesting that the NS1-Tg mice are a useful model for human NIHF. We also generated another type of NS1-Tg mice, in which NS1 expression is regulated by the immunoglobulin promoter in B lymphocytes. They expressed NS1 mRNA in lymphoid cells, but expression of NS1 protein was undetectable. Up until 40 weeks of age, they did not develop any signs of RA or any other autoimmune diseases. Since their expression of NS1 may be too low to induce any pathology in these mice, we are trying to generate other lines of NS1-Tg mice, which express higher amounts of NS1.

Research Products

• [Journal Article] Parvovirus B19 infection induces apoptosis of erythroid cells in vitro and in vivo. (1999)
  • Author(s): Yaegashi, N., et al.
  • Journal Title: J.Infection 39 Pages: 68-76
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serologic study of human parvovirus B19 infection in pregnancy in Japan. (1999)
  • Author(s): Yaegashi, N., et al.
  • Journal Title: J.Infection 38 Pages: 30-35
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serologic Study of Human Parvovirus B19 Infection in Pregnancy in Japan, (1999)
  • Author(s): Yaegashi, N., Niinuma, T., Chisaka, H., Uehara, S., Okamura, K., Shinkawa, O., Tsunoda, A., Moffatt, S., Sugamura, K.Yajima, A.
  • Journal Title: J.Infection Vol.38 Pages: 30-35
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Parvovirus B19 induces poptosis of erythroid cells in vitro and in vivo. (1999)
  • Author(s): Yaegashi, N., Niinuma, T., Chisaka, H., Uehara, S., Moffatt, S., Tada, K., Iwabuchi, M., Matsunaga Y., Nakayama, M., Yutani, C., Osamura, Y., Hirayama, E., Okamura, K., Sugamura, K., Yajima, A.
  • Journal Title: J.Infection Vol.39 Pages: 68-76
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human parvovirus B19 as a causative agent for rheumatoid arthritis. (1998)
  • Author(s): Takahashi, Y., et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA 95・14 Pages: 8227-8232
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human parvovirus B19 as a causative agent for rheumatoid arthritis. (1998)
  • Author(s): Takahashi, Y., Murai, C., Shibata, S., Munakata, Y., Ishii, T., Ishii, K., Saitoh, T., Sawai, T., Sugamura, K., Sasaki, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA, Vol.95, 14 Pages: 8227-8232
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 八重樫伸生、他8名: "Serologic study of human parvovirus B19 infection in pregnancy in Japan"J. Infection. 38. 30-35 (1999)
• [Publications] 浅田洋司 他9名: "Grf40, a novel Grb2 family member, is involved in T-cell signaling through interaction with SLP-76 and LAT"J. Exp. Med.. 189. 1383-1390 (1999)
• [Publications] 田中伸幸 他7名: "Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediated vy cytokines.J"J. Biol. Chem.. 274. 19129-19135 (1999)
• [Publications] 阿部弘幸 他8名: "Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene"Gene. 227. 71-77 (1999)
• [Publications] Takahashi,Y.: "Human parvovirus B19 as a causative agent for rheumatoid arthritis." Proc.Natl.Acad.Sci.USA. 95. 8227-8232 (1998)
• [Publications] Yaegashi,N.: "The incidence of,and factors leading to,parvovirus B19-related hydrops fetalis following maternal infection:report of 10 cases and meta-analysis." J.Infection. 37. 28-35 (1998)
• [Publications] Ohtani,K.,et.al.: "Molecular mechanisms of promoter regulation of the gp34 gene that is trans-activated by an opcoprotein Tax of human T-cell leukemia virus type 1." J.Biol.Chem.273. 14119-14129 (1998)
• [Publications] Moffatt,S.: "Human parvovirus B19 nonstructural(NS1)protein induces apoptosis in erythroid lineagecells." J.Virol.72. 3018-3028 (1998)