Faculty Profiles - KIMURA, Hiroshi

Papers - KIMURA, Hiroshi

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Defective Epstein-Barr virus in chronic active infection and haematological malignancy Reviewed International coauthorship

Okuno Yusuke, Murata Takayuki, Sato Yoshitaka, Muramatsu Hideki, Ito Yoshinori, Watanabe Takahiro, Okuno Tatsuya, Murakami Norihiro, Yoshida Kenichi, Sawada Akihisa, Inoue Masami, Kawa Keisei, Seto Masao, Ohshima Koichi, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Miyano Satoru, Narita Yohei, Yoshida Masahiro, Goshima Fumi, Kawada Jun-Ichi, Nishida Tetsuya, Kiyoi Hitoshi, Kato Seiichi, Nakamura Shigeo, Morishima Satoko, Yoshikawa Tetsushi, Fujiwara Shigeyoshi, Shimizu Norio, Isobe Yasushi, Noguchi Masaaki, Kikuta Atsushi, Iwatsuki Keiji, Takahashi Yoshiyuki, Kojima Seiji, Ogawa Seishi, Kimura Hiroshi

NATURE MICROBIOLOGY Vol. 4 ( 3 ) page： 404 - 413 2019.3

The landscape of 142 Epstein-Barr viral whole genomes in gastric cancer

Kojima, Y; Hamada, M; Naruse, A; Goto, K; Khine, HT; Arai, H; Akutsu, Y; Satou, A; Nakaguro, M; Kato, S; Kodera, Y; Yatabe, Y; Torii, Y; Kawada, JI; Murata, T; Kimura, H; Takiguchi, S; Inagaki, H; Kataoka, H; Okuno, Y

JOURNAL OF GASTROENTEROLOGY Vol. 60 ( 1 ) page： 55 - 65 2025.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Gastroenterology

Background: A substantial portion of gastric cancer (GC) is linked to Epstein–Barr virus (EBV) infection. The characteristics of this viral genome, such as specific viral strains and large structural variations, influence the progression of diseases like nasopharyngeal carcinoma and hematological malignancy. However, the EBV genomes from GC have not been thoroughly characterized. Methods: Our study involved 849 consecutive GC patients diagnosed at Nagoya City University Hospital, Japan (NCU cohort). We detected EBV from formalin-fixed, paraffin-embedded sections using a novel direct PCR-based rapid detection method. Additionally, we analyzed 142 EBV whole genomes (125 newly sequenced) from GC, comparing them with 205 genomes from other EBV-associated diseases. Results: We identified 32 (3.8%) patients associated with EBVaGC in the NCU cohort. Moreover, the direct PCR identified several GC specimens containing EBV-infected lymphocytes or their follicles. The dominant viral strain in GC was type 1 EBV, prevalent in most parts of the world, and no GC-specific strain was identified. We found no significant associations between single-nucleotide variants in the viral genome and GC. Structural variations of the EBV genome were infrequent in GC (4 cases, 2.1%), contrasting with EBV-associated hematological malignancy, which frequently carries large deletions. Conclusions: This study is the first to uncover the genomic variations of EBV in GC. While EBV is definitively linked to GC, the characteristics of its genomes do not strongly correlate with disease development or progression. Our findings on viral genomes supplement the current understanding of human genomes in EBVaGC.

DOI： 10.1007/s00535-024-02170-3

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特集小児臨床検査2024 XIII.感染症検査 4.ウイルス感染症　2)ヘルペスウイルス感染症 Invited

鈴木高子, 木村宏

小児内科 Vol. 56 ( 13 ) page： 620 - 624 2024.10

Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection (vol 11 , 575255, 2021) International coauthorship Open Access

Inagaki, T; Sato, Y; Ito, J; Takaki, M; Okuno, Y; Yaguchi, M; Al Masud, HMA; Watanabe, T; Sato, K; Iwami, S; Murata, T; Kimura, H

FRONTIERS IN MICROBIOLOGY Vol. 15 page： 1426311 2024.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Microbiology

In the published article, there was an error in Table 2 as published. We have carelessly swapped the rows and columns of Table 2. The corrected Table 2 and its caption appear below. Estimated parameters by fitting the mathematical model to experimental data. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

DOI： 10.3389/fmicb.2024.1426311

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis

Suzuki, T; Sato, Y; Okuno, Y; Torii, Y; Fukuda, Y; Haruta, K; Yamaguchi, M; Kawamura, Y; Hama, A; Narita, A; Muramatsu, H; Yoshikawa, T; Takahashi, Y; Kimura, H; Ito, Y; Kawada, JI

JOURNAL OF CLINICAL IMMUNOLOGY Vol. 44 ( 4 ) page： 103 2024.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Immunology

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds, one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A—the gene responsible for XLP1—was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients’ background, indicating the key features of EBV-HLH.

DOI： 10.1007/s10875-024-01701-0

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Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation Open Access

Sagou, K; Sato, Y; Okuno, Y; Watanabe, T; Inagaki, T; Motooka, Y; Toyokuni, S; Murata, T; Kiyoi, H; Kimura, H

PLOS PATHOGENS Vol. 20 ( 2 ) page： e1011954 2024.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS Pathogens

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

DOI： 10.1371/journal.ppat.1011954

Updated guidelines for chronic active Epstein-Barr virus disease Open Access

Kawada, JI; Ito, Y; Ohshima, K; Yamada, M; Kataoka, S; Muramatsu, H; Sawada, A; Wada, T; Imadome, KI; Arai, A; Iwatsuki, K; Ohga, S; Kimura, H

INTERNATIONAL JOURNAL OF HEMATOLOGY Vol. 118 ( 5 ) page： 568 - 576 2023.11

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology

Chronic active Epstein–Barr virus disease (CAEBV), formerly named chronic active Epstein–Barr virus infection, is characterized by systemic inflammation and clonal proliferation of Epstein–Barr virus (EBV)-infected T or NK cells. As CAEBV is a potentially life-threatening illness, appropriate diagnosis and therapeutic interventions are necessary for favorable clinical outcomes. Substantial evidence regarding the pathogenesis and treatment of CAEBV has been accumulated since previous guidelines for the diagnosis of CAEBV were proposed. To reflect this evidence, we updated the guidelines for the diagnosis and treatment of CAEBV to improve clinical management of the disease. The details of the updated guidelines are presented in this report. Diagnosis of CAEBV now requires confirmation of a high copy number of EBV genome and EBV-infected T or NK cells. An EBV DNA load ≥ 10,000 IU/mL in whole blood is proposed as the diagnostic cutoff value for CAEBV in this updated guideline. A standard treatment approach for CAEBV has not been established, and hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment. Chemotherapy can be administered to control disease activity before HSCT.

DOI： 10.1007/s12185-023-03660-5

Correction: "The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms" Leukemia. 2022 Jul;36(7):1720-1748. International coauthorship Open Access

Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, de Oliveira Araujo IB, Berti E, Bhagat G, Borges AM, Boyer D, Calaminici M, Chadburn A, Chan JKC, Cheuk W, Chng WJ, Choi JK, Chuang SS, Coupland SE, Czader M, Dave SS, de Jong D, Di Napoli A, Du MQ, Elenitoba-Johnson KS, Ferry J, Geyer J, Gratzinger D, Guitart J, Gujral S, Harris M, Harrison CJ, Hartmann S, Hochhaus A, Jansen PM, Karube K, Kempf W, Khoury J, Kimura H, Klapper W, Kovach AE, Kumar S, Lazar AJ, Lazzi S, Leoncini L, Leung N, Leventaki V, Li XQ, Lim MS, Liu WP, Louissaint A Jr, Marcogliese A, Medeiros LJ, Michal M, Miranda RN, Mitteldorf C, Montes-Moreno S, Morice W, Nardi V, Naresh KN, Natkunam Y, Ng SB, Oschlies I, Ott G, Parrens M, Pulitzer M, Rajkumar SV, Rawstron AC, Rech K, Rosenwald A, Said J, Sarkozy C, Sayed S, Saygin C, Schuh A, Sewell W, Siebert R, Sohani AR, Suzuki R, Tooze R, Traverse-Glehen A, Vega F, Vergier B, Wechalekar AD, Wood B, Xerri L, Xiao W, International Agency for Research on Cancer/World Health Organization

Leukemia Vol. 37 ( 9 ) page： 1944 - 1951 2023.9

Growth Transformation of B Cells by Epstein-Barr Virus Requires IMPDH2 Induction and Nucleolar Hypertrophy International coauthorship Open Access

Sugimoto, A; Watanabe, T; Matsuoka, K; Okuno, Y; Yanagi, Y; Narita, Y; Mabuchi, S; Nobusue, H; Sugihara, E; Hirayama, M; Ide, T; Onouchi, T; Sato, Y; Kanda, T; Saya, H; Iwatani, Y; Kimura, H; Murata, T

MICROBIOLOGY SPECTRUM Vol. 11 ( 4 ) page： e0044023 2023.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Microbiology Spectrum

The in vitro growth transformation of primary B cells by Epstein-Barr virus (EBV) is the initial step in the development of posttransplant lymphoproliferative disorder (PTLD). We performed electron microscopic analysis and immunostaining of primary B cells infected with wild-Type EBV. Interestingly, the nucleolar size was increased by two days after infection. A recent study found that nucleolar hypertrophy, which is caused by the induction of the IMPDH2 gene, is required for the efficient promotion of growth in cancers. In the present study, RNA-seq revealed that the IMPDH2 gene was significantly induced by EBV and that its level peaked at day 2. Even without EBV infection, the activation of primary B cells by the CD40 ligand and interleukin-4 increased IMPDH2 expression and nucleolar hypertrophy. Using EBNA2 or LMP1 knockout viruses, we found that EBNA2 and MYC, but not LMP1, induced the IMPDH2 gene during primary infections. IMPDH2 inhibition by mycophenolic acid (MPA) blocked the growth transformation of primary B cells by EBV, leading to smaller nucleoli, nuclei, and cells. Mycophenolate mofetil (MMF), which is a prodrug of MPA that is approved for use as an immunosuppressant, was tested in a mouse xenograft model. Oral MMF significantly improved the survival of mice and reduced splenomegaly. Taken together, these results indicate that EBV induces IMPDH2 expression through EBNA2-dependent and MYC-dependent mechanisms, leading to the hypertrophy of the nucleoli, nuclei, and cells as well as efficient cell proliferation. Our results provide basic evidence that IMPDH2 induction and nucleolar enlargement are crucial for B cell transformation by EBV. In addition, the use of MMF suppresses PTLD. IMPORTANCE EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).

DOI： 10.1128/spectrum.00440-23

Diagnostic and disease severity determination criteria for hydroa vacciniforme lymphoproliferative disorders and severe mosquito bite allergy Open Access

Hirai, Y; Asada, H; Hamada, T; Kawada, J; Kimura, H; Arai, A; Ohshima, K; Ohga, S; Iwatsuki, K

JOURNAL OF DERMATOLOGY Vol. 50 ( 7 ) page： E198 - E205 2023.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Dermatology

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) and severe mosquito bite allergy (SMBA) are both cutaneous forms of Epstein–Barr virus (EBV)-associated T/natural killer (NK) cell LPDs and are closely related to chronic active EBV disease (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). HV-LPD is further divided into classic HV, a benign subtype mediated by EBV-positive γδT cells, and systemic HV, another life-threatening subtype mainly associated with EBV-positive αβT or γδT cells. The vast majority of patients with SMBA have increased numbers of EBV-infected NK cells in the blood. Clinical symptoms of HV-LPD and SMBA often overlap in the same patient and may progress to more serious disease conditions equivalent to the systemic form of CAEBV. To define the disease spectrum of HV-LPD and SMBA, we propose the diagnostic criteria and the determination criteria for disease severity. The proposed diagnostic criteria are consistent with those for CAEBV and EBV-HLH in the guidelines for the management for CAEBV and related disorders 2023.

DOI： 10.1111/1346-8138.16842

Epstein-Barr Virus BBLF1 Mediates Secretory Vesicle Transport to Facilitate Mature Virion Release Open Access

Uddin, MK; Watanabe, T; Arata, M; Sato, Y; Kimura, H; Murata, T

JOURNAL OF VIROLOGY Vol. 97 ( 6 ) page： e0043723 2023.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Virology

Enveloped viruses undergo a complex multistep process of assembly, maturation, and release into the extracellular space utilizing host secretory machinery. Several studies of the herpesvirus subfamily have shown that secretory vesicles derived from the trans-Golgi network (TGN) or endosomes transport virions into the extracellular space. However, the regulatory mechanism underlying the release of Epstein-Barr virus, a human oncovirus, remains unclear. We demonstrate that disruption of BBLF1, a tegument component, suppressed viral release and resulted in the accumulation of viral particles on the inner side of the vesicular membrane. Organelle separation revealed the accumulation of infectious viruses in fractions containing vesicles derived from the TGN and late endosomes. Deficiency of an acidic amino acid cluster in BBLF1 reduced viral secretion. Moreover, truncational deletion of the C-terminal region of BBLF1 increased infectious virus production. These findings suggest that BBLF1 regulates the viral release pathway and reveal a new aspect of tegument protein function.

DOI： 10.1128/jvi.00437-23

特集新しい時代の小児感染症各論:原因微生物別ウイルスヘルペスウイルス科 Invited

川田潤一, 木村宏

小児内科 Vol. 55 ( 4 ) page： 623 - 628 2023.4

Salvage Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplant With Posttransplant Cyclophosphamide for Graft Failure in a Patient With Chronic Active Epstein-Barr Virus Infection

Nakaya, Y; Koh, H; Harada, N; Okamura, H; Misugi, T; Suekane, T; Tachibana, D; Kimura, H; Hino, M; Nakamae, H

EXPERIMENTAL AND CLINICAL TRANSPLANTATION Vol. 21 ( 2 ) page： 184 - 188 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Experimental and Clinical Transplantation

Salvage human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide has shown promising results for graft failure in various hematological disorders. However, to our knowledge, no such findings have been reported for a case of chronic active Epstein-Barr virus infection, although graft failure is relatively common in patients with chronic active Epstein-Barr virus infection. We report a case of a 32-year-old woman with natural killer-cell type chronic active Epstein-Barr virus infection who experienced graft failure after a first allogeneic hematopoietic cell transplant from an unrelated human leukocyte antigen-matched donor. The patient received a second allogeneic hematopoietic cell transplant with human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide (cyclophosphamide, 50 mg/kg, on day 3 and day 4) following reduced-intensity conditioning as rescue therapy. Neutrophils successfully engrafted on day 19, and the patient sustained remission without severe transplant-related complication 10 months after salvage human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide. This report suggests that salvage human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide may be a feasible therapeutic option for graft failure in patients with chronic active Epstein-Barr virus infection.

DOI： 10.6002/ect.2022.0322

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症例 CD8＋αβT細胞優位型種痘様水疱症リンパ増殖異常症の1例

大林三裕佳, 中村賢人, 古橋卓也, 岩月啓氏, 三宅智子, 平井陽至, 谷田けい, 金兼弘和, 西田徹也, 木村宏, 森田明理

皮膚科の臨床 Vol. 65 ( 2 ) page： 273 - 278 2023.2

N6-methyladenosine Modification of Hepatitis B Virus RNA in the Coding Region of HBx Open Access

Murata, T; Iwahori, S; Okuno, Y; Nishitsuji, H; Yanagi, Y; Watashi, K; Wakita, T; Kimura, H; Shimotohno, K

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 24 ( 3 ) 2023.2

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences

N6-methyladenosine (m6A) is a post-transcriptional modification of RNA involved in transcript transport, degradation, translation, and splicing. We found that HBV RNA is modified by m6A predominantly in the coding region of HBx. The mutagenesis of methylation sites reduced the HBV mRNA and HBs protein levels. The suppression of m6A by an inhibitor or knockdown in primary hepatocytes decreased the viral RNA and HBs protein levels in the medium. These results suggest that the m6A modification of HBV RNA is needed for the efficient replication of HBV in hepatocytes.

DOI： 10.3390/ijms24032265

The 100th anniversary of the Nagoya Journal of Medical Science: a message from the Dean

Kimura, H

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 85 ( 1 ) page： 5 - 6 2023.2

The Epstein-Barr Virus Enhancer Interaction Landscapes in Virus-Associated Cancer Cell Lines International coauthorship Open Access

Ding Weiyue, Wang Chong, Narita Yohei, Wang Hongbo, Leong Merrin Man Long, Huang Alvin, Liao Yifei, Liu Xuefeng, Okuno Yusuke, Kimura Hiroshi, Gewurz Benjamin, Teng Mingxian, Jin Shuilin, Sato Yoshitaka, Zhao Bo

JOURNAL OF VIROLOGY Vol. 96 ( 18 ) page： e0073922 2022.9

EBV-associated NK and T-cell lymphoid neoplasms. International coauthorship Open Access

Kimura H, de Leval L, Cai Q, Kim WS

Current opinion in oncology Vol. 34 ( 5 ) page： 422 - 431 2022.9

Comprehensive Analyses of Intraviral Epstein-Barr Virus Protein-Protein Interactions Hint Central Role of BLRF2 in the Tegument Network International coauthorship Open Access

Hara Yuya, Watanabe Takahiro, Yoshida Masahiro, Al Masud H. M. Abdullah, Kato Hiromichi, Kondo Tomohiro, Suzuki Reiji, Kurose Shutaro, Uddin Md Kamal, Arata Masataka, Miyagi Shouhei, Yanagi Yusuke, Sato Yoshitaka, Kimura Hiroshi, Murata Takayuki

JOURNAL OF VIROLOGY Vol. 96 ( 14 ) page： e0051822 2022.7

Genome-wide CRISPR screen for HSV-1 host factors reveals PAPSS1 contributes to heparan sulfate synthesis Open Access

Suzuki Takeshi, Sato Yoshitaka, Okuno Yusuke, Goshima Fumi, Mikami Tadahisa, Umeda Miki, Murata Takayuki, Watanabe Takahiro, Watashi Koichi, Wakita Takaji, Kitagawa Hiroshi, Kimura Hiroshi

COMMUNICATIONS BIOLOGY Vol. 5 ( 1 ) page： 694 2022.7

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Papers - KIMURA, Hiroshi