研究者業績

村田 一素

Kazumoto Murata

基本情報

所属
自治医科大学 感染・免疫学講座ウイルス学部門 教授

J-GLOBAL ID
201801011769435239
researchmap会員ID
B000317781

学歴

 1

主要な論文

 217
  • Kazumoto Murata, Senko Tsukuda, Futoshi Suizu, Akihiro Kimura, Masaya Sugiyama, Koichi Watashi, Masayuki Noguchi, Masashi Mizokami
    Hepatology 71(5) 1533-1545 2020年5月  査読有り筆頭著者
    BACKGROUND AND AIMS: Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs. APPROACH AND RESULTS: This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production. CONCLUSIONS: Among NUCs, only ANPs have an additional pharmacological effect modulating LPS-mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.
  • Kazumoto Murata, Jong-Hon Kang, Shigeo Nagashima, Takeshi Matsui, Yoshiyasu Karino, Yoshiya Yamamoto, Tomofumi Atarashi, Masatsugu Oohara, Minoru Uebayashi, Hidekatsu Sakata, Keiji Matsubayashi, Kazuaki Takahashi, Masahiro Arai, Shunji Mishiro, Masaya Sugiyama, Masashi Mizokami, Hiroaki Okamoto
    Cytokine 125 154816-154816 2020年1月  査読有り
    Background and aim: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodbome. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-lambda 3) in acute hepatitis E.Methods: IFN-lambda 3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively.Results: High serum IFN-lambda 3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-lambda 3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-lambda 3 induction (Caco-2, A549) and recombinant IFN-lambda 3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-lambda 3 in a titer-dependent manner.Conclusions: These clinical and experimental observations suggest that HEV induced IFN-lambda 3 as a host innate immune response, which may play a protective role against HEV.
  • Kazumoto Murata, Mai Asano, Akihiro Matsumoto, Masaya Sugiyama, Nao Nishida, Eiji Tanaka, Taisuke Inoue, Minoru Sakamoto, Nobuyuki Enomoto, Takayoshi Shirasaki, Masao Honda, Shuichi Kaneko, Hiroyuki Gatanaga, Shinichi Oka, Yuki I Kawamura, Taeko Dohi, Yasutaka Shuno, Hideaki Yano, Masashi Mizokami
    Gut 67(2) 362-371 2018年2月  査読有り筆頭著者
    <sec><title>Objective</title>The clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration. </sec><sec><title>Design</title>Serum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated. </sec><sec><title>Results</title>Higher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells. </sec><sec><title>Conclusions</title>We discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target. </sec>
  • Kazumoto Murata, Masaya Sugiyama, Tatsuji Kimura, Sachiyo Yoshio, Tatsuya Kanto, Ikue Kirikae, Hiroaki Saito, Yoshihiko Aoki, Satoshi Hiramine, Teppei Matsui, Kiyoaki Ito, Masaaki Korenaga, Masatoshi Imamura, Naohiko Masaki, Masashi Mizokami
    Journal of Gastroenterology 49(1) 126-137 2014年1月  査読有り筆頭著者
  • SUZUKI Hideto, MURATA Kazumoto, GOTOH Takaya, KUSANO Masao, OKANO Hiroshi, OYAMADA Takashi, YASUDA Yoshikazu, IMAMURA Masatoshi, KUDO Masatoshi, MIZOKAMI Masashi, SAKAMOTO Atsushi
    Journal of gastroenterology 46(10) 1219-1229 2011年10月  査読有り責任著者
  • Kazumoto Murata, Masami Moriyama
    Cancer Research 67(7) 3263-3268 2007年4月1日  査読有り筆頭著者
  • Kazumoto Murata, Minoru Hamada, Kazushi Sugimoto, Takeshi Nakano
    Journal of Hepatology 46(2) 322-329 2007年2月  査読有り筆頭著者
  • K. Murata, M. Lechmann, M. Qiao, T. Gunji, H. J. Alter, T. J. Liang
    Proceedings of the National Academy of Sciences 100(11) 6753-6758 2003年5月27日  査読有り筆頭著者
  • Jujin Satoi, Kazumoto Murata, Martin Lechmann, Elanchezhiyan Manickan, Zhensheng Zhang, Heiner Wedemeyer, Barbara Rehermann, T. Jake Liang
    Journal of Virology 75(24) 12121-12127 2001年12月15日  査読有り筆頭著者
    <title>ABSTRACT</title> To study the effect of genetic immunization on transgenic expression of hepatitis C virus (HCV) proteins, we evaluated the immunological response of HCV transgenic mice to HCV expression plasmids. FVB/n transgenic mice expressing HCV structural proteins (core, E1, and E2) and wild-type (WT) FVB/n mice were immunized intramuscularly with plasmids expressing core (pHCVcore) or core/E1/E2 (pHCVSt). After immunization, HCV-specific humoral and cellular immune response was studied. Both WT and transgenic mice immunized with either HCV construct produced antibodies and exhibited T-cell proliferative responses against core or envelope. In WT mice immunized with pHCVSt, cytotoxic T-lymphocyte (CTL) activities were detected against E2 but not against core or E1, whereas strong CTL activities against core could be detected in WT mice immunized with pHCVcore. In pHCVSt-immunized, transgenic mice, CTL activities against the core or envelope were completely absent, but core-specific CTL activities could be detected in pHCVcore-immunized transgenic mice. A similar pattern of immune responses was also observed in other mouse strains, including a transgenic line expressing human HLA-A2.1 molecules (AAD mice). Despite the presence of a peripheral cellular immunity against HCV, no liver pathology or lymphocytic infiltrate was observed in these transgenic mice. Our study suggests a hierarchy of CTL response against the HCV structural proteins (E2 &gt; core &gt; E1) in vivo when the proteins are expressed as a polyprotein. The HCV transgenic mice can be induced by DNA immunization to generate anti-HCV antibodies and anticore CTLs. However, they are tolerant at the CTL level against the E2 protein despite DNA immunization.
  • Lechmann M, Murata K, Satoi J, Vergalla J, Baumert TF, Liang TJ
    Hepatology 34(2) 417-423 2001年8月  査読有り

MISC

 35

共同研究・競争的資金等の研究課題

 13