Research for innate immune system sensor molecules in HBV infection

• Project/Area Number: 16K19324
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: NAKAI MASATO 北海道大学, 大学病院, 助教 (40756003)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: B型肝炎ウイルス / DNAセンサー / 内科 / 消化器病学 / 免疫学

Outline of Final Research Achievements

In acute HBV infection phase, it takes time for the virus to grow and liver damage to appear, but the nucleic acid recognition for HBV-DNA and mechanism of innate immunity during that period are not well understood. In chronic HBV infection, immunologically tolerated state is established, and complete elimination of the virus is difficult because HBV covalently closed circular DNA (cccDNA) remains in the nucleus for life. Based on the above,the purpose of this study was to investigate the role of intracellular DNA sensor molecules in HBV infection, the effect on HBV-DNA replication, and the immune response. Focusing on various DNA sensor molecules, especially DDX41, we analyzed the expression in various hepatocyte cell lines, In NTCP-C4-HepG2 cells in which DDX41 was constitutively knocked down, HBV-DNA and RNA increased in an early stage compared with the control. This results suggested that DDX41 suppresses HBV proliferation in hepatocytes.

Academic Significance and Societal Importance of the Research Achievements

HBVの完全な排除はまだ臨床的に達成されていないこと、その自然免疫応答はいまだ理解されていない点が多い。本研究ではDDX41分子がHBV感染に関与していることが示唆されるデータを得られている。DDX41のHBV感染に関しての報告は多くないため、本研究をさらに進めることで、HBV感染へのDDX41の関与を明らかにし、自然免疫応答やウイルス排除へのさらなる知見の蓄積が可能となる可能性がある。

Research Products

• [Journal Article] Glecaprevir and Pibrentasvir for Japanese Patients with Human Immunodeficiency Virus and Genotype 3 Hepatitis C Virus Coinfection: A Report of Three Cases (2019)
  • Author(s): Sho Takuya、Suda Goki、Kimura Megumi、Shimazaki Tomoe、Maehara Osamu、Shigesawa Taku、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Umemura Machiko、Izumi Takaaki、Kawagishi Naoki、Baba Masaru、Nakai Masato、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya、for the NORTE Study Group
  • Journal Title: Internal Medicine Volume: 58 Issue: 6 Pages: 797-802
  • DOI: 10.2169/internalmedicine.1856-18
  • NAID: 130007611402
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Entecavir treatment of hepatitis B virus‐infected patients with severe renal impairment and those on hemodialysis (2019)
  • Author(s): Suzuki Kazuharu、Suda Goki、Yamamoto Yoshiya、Furuya Ken、Baba Masaru、Kimura Megumi、Maehara Osamu、Shimazaki Tomoe、Yamamoto Koji、Shigesawa Taku、Nakamura Akihisa、Ohara Masatsugu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya、for the NORTE Study Group
  • Journal Title: Hepatology Research Volume: 49 Issue: 11 Pages: 1294-1304
  • DOI: 10.1111/hepr.13399
  • Peer Reviewed
• [Journal Article] Assessing the risk of hepatocellular carcinoma by combining liver stiffness and the controlled attenuation parameter (2019)
  • Author(s): Izumi Takaaki、Sho Takuya、Morikawa Kenichi、Shigesawa Taku、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Kawagishi Naoki、Umemura Machiko、Shimazaki Tomoe、Kimura Megumi、Nakai Masato、Suda Goki、Natsuizaka Mitsuteru、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Ono Kota、Baba Masaru、Furuya Ken、Sakamoto Naoya
  • Journal Title: Hepatology Research Volume: 49 Issue: 10 Pages: 1207-1217
  • DOI: 10.1111/hepr.13391
  • Peer Reviewed
• [Journal Article] Quantifying Protein-Specific N-Glycome Profiles by Focused Protein and Immunoprecipitation Glycomics (2019)
  • Author(s): Kobayashi Takashi、Ogawa Koji、Furukawa Jun-ichi、Hanamatsu Hisatoshi、Hato Megumi、Yoshinaga Tomoyo、Morikawa Kenichi、Suda Goki、Sho Takuya、Nakai Masato、Higashino Kenichi、Numata Yoshito、Shinohara Yasuro、Sakamoto Naoya
  • Journal Title: Journal of Proteome Research Volume: 18 Issue: 8 Pages: 3133-3141
  • DOI: 10.1021/acs.jproteome.9b00232
  • NAID: 120006876288
  • Peer Reviewed
• [Journal Article] Comparative Glycomic Analysis of Sialyl Linkage Isomers by Sialic Acid Linkage-Specific Alkylamidation in Combination with Stable Isotope Labeling of α2,3-Linked Sialic Acid Residues (2019)
  • Author(s): Hanamatsu Hisatoshi、Nishikaze Takashi、Tsumoto Hiroki、Ogawa Koji、Kobayashi Takashi、Yokota Ikuko、Morikawa Kenichi、Suda Goki、Sho Takuya、Nakai Masato、Miura Nobuaki、Higashino Kenichi、Sekiya Sadanori、Iwamoto Shinichi、Miura Yuri、Furukawa Jun-ichi、Tanaka Koichi、Sakamoto Naoya
  • Journal Title: Analytical Chemistry Volume: 91 Issue: 21 Pages: 13343-13348
  • DOI: 10.1021/acs.analchem.9b03617
  • Peer Reviewed
• [Journal Article] Safety and efficacy of elbasvir and grazoprevir in Japanese hemodialysis patients with genotype 1b hepatitis C virus infection (2018)
  • Author(s): Suda Goki、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya、他
  • Journal Title: Journal of Gastroenterology Volume: 54 Issue: 1 Pages: 78-86
  • DOI: 10.1007/s00535-018-1495-6
  • Peer Reviewed
• [Journal Article] L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis (2018)
  • Author(s): Ohara Masatsugu、Ogawa Koji、Suda Goki、Kimura Megumi、Maehara Osamu、Shimazaki Tomoe、Suzuki Kazuharu、Nakamura Akihisa、Umemura Machiko、Izumi Takaaki、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Hepatology Communications Volume: 2 Issue: 8 Pages: 906-918
  • DOI: 10.1002/hep4.1207
  • NAID: 120006585791
  • Peer Reviewed / Open Access
• [Journal Article] Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis (2018)
  • Author(s): Kawagishi Naoki、Suda Goki、Nakamura Akinobu、Kimura Megumi、Maehara Osamu、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Izumi Takaaki、Umemura Machiko、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Miyoshi Hideaki、Sakamoto Naoya
  • Journal Title: PLOS ONE Volume: 13 Issue: 12 Pages: 615-620
  • DOI: 10.1371/journal.pone.0209615
  • NAID: 120006866533
  • Peer Reviewed / Open Access
• [Journal Article] Increased serum C-reactive protein and decreased urinary aquaporin 2 levels are predictive of the efficacy of tolvaptan in patients with liver cirrhosis (2018)
  • Author(s): 3.Nakai M, Ogawa K, Takeda R, Ohara M, Kawagishi N, Izumi T, Umemura M, Ito J, Sho T, Suda G, Morikawa K, Sakamoto N
  • Journal Title: Hepatolgy Research Volume: in press Issue: 3
  • DOI: 10.1111/hepr.12988
  • NAID: 120006551584
  • Peer Reviewed
• [Journal Article] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C (2017)
  • Author(s): Kawagishi N.、Suda G.、Onozawa M.、Kimura M.、Maehara O.、Ohara M.、Izumi T.、Umemura M.、Ito J.、Nakai M.、Sho T.、Natsuizaka M.、Morikawa K.、Ogawa K.、Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: 24 Issue: 12 Pages: 1098-1106
  • DOI: 10.1111/jvh.12737
  • Peer Reviewed