Research of activation mechanism and pathogenicity of CIHHV-6

• Project/Area Number: 20K17460
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Endo Akifumi 東京医科歯科大学, 東京医科歯科大学病院, プロジェクト助教 (80624238)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CIHHV-6 / HHV-6 / immunodeficiency

Outline of Research at the Start

Human herpesvirus-6（HHV-6）は、けいれん発作や脳炎などに関わるDNAウイルスである。1990年代にこのHHV-6 がヒトゲノムの生殖細胞系に組み込まれる事（Chromosomally integrated HHV-6:CIHHV-6)が発見され、その後人口の約1％が保持している事が分かってきた。研究者は、このCIHHV-6が体内で活性化し病原性を有する事をウイルス学的および分子生物学的に確認し報告してきた。しかし詳細な活性化機構は未だ解明されておらず、またHHV-6が組み込まれる機構も未解明のままである。本研究では、これらの機構の解明を目指している。

Outline of Final Research Achievements

In this study, we aimed to elucidate the activation mechanism of CIHHV-6. We collected clinical information and samples from patients with CIHHV-6. We constructed an immunodeficiency registry in Japan, identified CIHHV-6 patients, and collected clinical specimens and clinical information. Also, during the research period, the social impact of COVID-19 was significant, so we cooperated with those studies. In our case of CIHHV-6, activation was observed in an immunodeficient patient with a single-gene IL2RG abnormality, and in order to verify whether the corresponding gene was involved in the activation mechanism, an immortalized cell line was established from the patient's family specimen. We studied the establishment of a system that knocks down IL2RG.But it is difficult to establish the system, and we are examining the conditions.

Academic Significance and Societal Importance of the Research Achievements

CIHHV-6患者さんを含んだ本邦の免疫不全レジストリを構築することができた。
また研究期間中はCOVID-19の社会的影響が大きかったため、それらの研究へ貢献した。CIHHV-6 症例からもEBVによる不死化細胞株の樹立が確認できた。
しかしノックダウンする系の立ち上げは通常の細胞よりも難しいことが確認された。

Research Products

• [Journal Article] The Primary Immunodeficiency Database in Japan (2022)
  • Author(s): Mitsui-Sekinaka Kanako、Sekinaka Yujin、Endo Akifumi、Imai Kohsuke、Nonoyama Shigeaki
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 805766-805766
  • DOI: 10.3389/fimmu.2021.805766
  • Peer Reviewed / Open Access
• [Journal Article] Neutralizing Type I Interferon Autoantibodies in Japanese Patients with Severe COVID-19 (2022)
  • Author(s): Eto S, Nukui Y, Tsumura M, Nakagama Y, Kashimada K, Mizoguchi Y, Utsumi T, Taniguchi M, Sakura F, Noma K, Yoshida Y, Ohshimo S, Nagashima S, Okamoto K, Endo A, Imai K, Kanegane H, Ohnishi H, Hirata S, Sugiyama E, Shime N, Ito M, Ohge H, Kido Y, Bastard P, Casanova JL, Ohara O, Tanaka J, Morio T, Okada S
  • Journal Title: Journal of Clinical Immunology Volume: 42 Issue: 7 Pages: 1360-1370
  • DOI: 10.1007/s10875-022-01308-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force (2022)
  • Author(s): Wang Qingbo S.、et al.
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 4830-4830
  • DOI: 10.1038/s41467-022-32276-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19 (2021)
  • Author(s): Asano Takaki、Boisson Bertrand、Onodi Fanny, et al.
  • Journal Title: Science Immunology Volume: 6 Issue: 62
  • DOI: 10.1126/sciimmunol.abl4348
  • Peer Reviewed
• [Journal Article] Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases (2021)
  • Author(s): Nishimura Akira、Aoki Yuki、Ishiwata Yasuyoshi、・・・Endo Akifumi、Yasuhara Masato、Kamiya Takahiro、Mitsuiki Noriko、Ono Toshiaki、Isoda Takeshi、Yanagimachi Masakatsu、Tomizawa Daisuke、Nagasawa Masayuki、Mizutani Shuki、Kajiwara Michiko、Takagi Masatoshi、Kanegane Hirokazu、Imai Kohsuke、Morio Tomohiro
  • Journal Title: Journal of Clinical Immunology Volume: online Issue: 5 Pages: 944-957
  • DOI: 10.1007/s10875-021-00966-z
  • Peer Reviewed
• [Journal Article] Association between Immunoglobulin M and Steroid Resistance in Children with Nephrotic Syndrome: A Retrospective Multicenter Study in Japan (2021)
  • Author(s): Udagawa T, Matsuyama Y, Okutsu M, Motoyoshi Y, Okada M, Tada N, Kikuchi E, Shimoda M, Kanamori T, Omori T, Takahashi M, Imai K,Endo A, Fujiwara T and Morio T
  • Journal Title: Kidney360 Volume: 2021 Issue: 3 Pages: 487-493
  • DOI: 10.34067/kid.0004432020
  • Peer Reviewed / Open Access
• [Journal Article] Cytomegalovirus Laryngitis in Primary Combined Immunodeficiency Diseases (2020)
  • Author(s): Inoue Maiko、Isoda Takeshi、Yamashita Motoi、Tomoda Takahiro、Inoue Kento、Okano Tsubasa、Ohkawa Teppei、Endo Akifumi、Mitsuiki Noriko、Kamiya Takahiro、Yanagimachi Masakatsu、Yamamoto Kouhei、Inaba Yuichiro、Sasaki Toru、Takagi Masatoshi、Kanegane Hirokazu、Imai Kohsuke、Morio Tomohiro
  • Journal Title: Journal of Clinical Immunology Volume: 41 Issue: 1 Pages: 243-247
  • DOI: 10.1007/s10875-020-00873-9
  • Peer Reviewed