論文 - 木村　宏

Defective Epstein-Barr virus in chronic active infection and haematological malignancy 査読有り 国際共著

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   4 巻 ( 3 ) 頁： 404 - 413   2019年3月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Microbiology  

DOI： 10.1038/s41564-018-0334-0

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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   60 巻 ( 1 ) 頁： 55 - 65   2025年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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 招待有り

鈴木 高子, 木村 宏

小児内科   56 巻 ( 13 ) 頁： 620 - 624   2024年10月

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：東京医学社  

DOI： 10.24479/pm.0000002022

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Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection (vol 11 , 575255, 2021) 国際共著 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   15 巻   頁： 1426311   2024年5月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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   44 巻 ( 4 ) 頁： 103   2024年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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   20 巻 ( 2 ) 頁： e1011954   2024年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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   118 巻 ( 5 ) 頁： 568 - 576   2023年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms (vol 36, pg 1720, 2022) 国際共著 Open Access

Alaggio, R; Amador, C; Anagnostopoulos, I; Attygalle, AD; Araujo, IBD; 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 ; 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, WB; Akinola, NO; Akkari, Y; Allende, LM; Aozasa, K; Araujo, I; Arcaini, L; Ardeshna, KM; Asano, N; Attarbaschi, A; Bacon, CM; Barrans, SL; Batchelor, T; Battistella, M; Baughn, LB; Behdad, A; Berentsen, S; Bianchi, G; Bledsoe, J; Borchmann, P; Bower, M; Buldini, B; Burger, JA; Burkhardt, B; Cassaday, RD; Cazzaniga, G; Cerf-Bensussan, N; Cesarman, E; Chandy, M; Chapman, JR; Chapuy, B; Chen, XY; Cheng, CL; Chiattone, C; Chiorazzi, N; Cook, LB; Cooper, WA; Corboy, GP; Cowan, AJ; Cozzolino, I; Cree, IA; d'Amore, ESG; Davies, AJ; Deckert, M; Delabie, J; Demicco, EG; Deshpande, V; Diepstra, A; Dierickx, D; Dunleavy, K; Eichhorst, B; Ennishi, D; Fajgenbaum, DC; Farinha, P; de Larrea, CF; Fisher, KE; Fitzgibbon, J; Flanagan, M; Fromm, J; Garcia, JF; Geddie, WR; Gertz, M; Gopal, A; Gopal, S; Greipp, PT; Gru, A; Gupta, R; Hansmann, ML; Hebeda, KM; Herfarth, K; Herling, M; Hermine, O; Khe, HX; Hodge, J; Hu, SM; Huang, YH; Hung, YP; Hunger, S; Inaba, H; Inagaki, H; Iqbal, J; Ishitsuka, K; Iwaki, N; Iwatsuki, K; Jain, N; Jeon, YK; Kadin, M; Kaji, S; Kakkar, A; Karadimitris, A; Kataoka, K; Kato, S; Kersten, MJ; Ketterling, RP; Kim, JE; Kratz, CP; Kridel, R; Kristinsson, S; Küppers, R; Kuzu, I; Kwong, YL; Lacasce, A; Lamant-Rochaix, L; Lamy, T; Landgren, O; Laskar, S; Laskin, WB; Lenz, G; Li, SY; Di Li, G; Lin, P; Locatelli, F; Lorsbach, RB; Lossos, I; Loughran, TP Jr; Macon, WR; Maleszewski, JJ; Malhotra, P; Marafioti, T; Maruyama, D; Marx, A; Mbulaiteye, SM; Meignin, V; Mejstrikova, E; Michelow, P; Miettinen, M; Miles, RR; Miyoshi, H; Molina, TJ; Mollejo, M; Momose, S; Mori, T; Morice, WG; Nadel, B; Nagai, H; Nagane, M; Nair, R; Nakamura, N; Nakazawa, A; Nasr, S; Nicholson, AG; Nicolae, A; Ohgami, RS; Oishi, N; Olson, TS; Ortonne, N; Paiva, B; Pan-Hammarström, Q; Parihar, M; Paulli, M; Petersen, A; Picarsic, J; Pileri, A; Pimpinelli, N; Plaza, JA; Rabin, KR; Raderer, M; Rai, K; Randen, U; Rao, H; Robson, A; Rochford, R; Rosenquist, R; Rossi, D; Rossi, ED; Rule, S; Rymkiewicz, G; Sabattini, E; Saha, V; Sakata-Yanagimoto, M; Sander, CA; Sangueza, JM; Sangüeza, OP; Santucci, M; Sato, Y; Satou, A; Schafernak, KT; Schmitt, F; Semenzato, G; Sengar, M; Shanafelt, T; Shimada, K; Slack, GW; Slager, S; Soffietti, R; Solomon, DA; Stamatopoulos, K; Steidl, C; Stilgenbauer, S; Sukswai, N; Takeuchi, K; Tallini, G; Tamaru, J; Tan, SY; Tembhare, P; Tiacci, E; Tokura, Y; Tournilhac, O; Treon, S; Truemper, L; Tsukasaki, K; van Rhee, F; Varghese, A; Vermeer, MH; Vielh, P; Walker, B; Wang, M; Wang, HY; Wang, Z; Watanabe, T; Weigert, O; Wein-Stock, D; Whittaker, SJ; Willemze, R; Woessmann, W; Wu, CJ; Yamaguchi, M; Yamamoto, H; Yamashita, D; Yang, SM; Yang, DT; Yasuda, T; Yin, WH; Zen, Y; Zhao, S; Zhao, WL

LEUKEMIA   37 巻 ( 9 ) 頁： 1944 - 1951   2023年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Leukemia  

Correction to: Leukemia, published online 22 June 2022 At the time of original publication, there was an incomplete listing of contributing authors and their institutions. This revision corrects those omissions.

DOI： 10.1038/s41375-023-01962-5

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Growth Transformation of B Cells by Epstein-Barr Virus Requires <i>IMPDH2</i> Induction and Nucleolar Hypertrophy 国際共著 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   11 巻 ( 4 ) 頁： e0044023   2023年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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   50 巻 ( 7 ) 頁： E198 - E205   2023年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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   97 巻 ( 6 ) 頁： e0043723   2023年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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 招待有り

川田 潤一, 木村 宏

小児内科   55 巻 ( 4 ) 頁： 623 - 628   2023年4月

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：東京医学社  

DOI： 10.24479/pm.0000000861

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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   21 巻 ( 2 ) 頁： 184 - 188   2023年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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   65 巻 ( 2 ) 頁： 273 - 278   2023年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：金原出版  

DOI： 10.18888/hi.0000003782

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N6-methyladenosine Modification of Hepatitis B Virus RNA in the Coding Region of <i>HBx</i> 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   24 巻 ( 3 )   2023年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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The 100<SUP>th</SUP> anniversary of the Nagoya Journal of Medical Science: a message from the Dean

Kimura, H

NAGOYA JOURNAL OF MEDICAL SCIENCE   85 巻 ( 1 ) 頁： 5 - 6   2023年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nagoya journal of medical science  

DOI： 10.18999/nagjms.85.1.5

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The Epstein-Barr Virus Enhancer Interaction Landscapes in Virus-Associated Cancer Cell Lines 国際共著 Open Access

Ding, WY; Wang, C; Narita, Y; Wang, HB; Leong, MML; Huang, A; Liao, YF; Liu, XF; Okuno, Y; Kimura, H; Gewurz, B; Teng, MX; Jin, SL; Sato, Y; Zhao, B

JOURNAL OF VIROLOGY   96 巻 ( 18 ) 頁： e0073922   2022年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Virology  

Epstein-Barr virus (EBV) persists in human cells as episomes. EBV episomes are chromatinized and their 3D conformation varies greatly in cells expressing different latency genes. We used HiChIP, an assay which combines genome-wide chromatin conformation capture followed by deep sequencing (Hi-C) and chromatin immunoprecipitation (ChIP), to interrogate the EBV episome 3D conformation in different cancer cell lines. In an EBV-transformed lymphoblastoid cell line (LCL) GM12878 expressing type III EBV latency genes, abundant genomic interactions were identified by H3K27ac HiChIP. A strong enhancer was located near the BILF2 gene and looped to multiple genes around BALFs loci. Perturbation of the BILF2 enhancer by CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) altered the expression of BILF2 enhancer-linked genes, including BARF0 and BALF2, suggesting that this enhancer regulates the expression of linked genes. H3K27ac ChIP followed by deep sequencing (ChIP-seq) identified several strong EBV enhancers in T/NK (natural killer) lymphoma cells that express type II EBV latency genes. Extensive intragenomic interactions were also found which linked enhancers to target genes. A strong enhancer at BILF2 also looped to the BALF loci. CRISPRi also validated the functional connection between BILF2 enhancer and BARF1 gene. In contrast, H3K27ac HiChIP found significantly fewer intragenomic interactions in type I EBV latency gene-expressing primary effusion lymphoma (PEL) cell lines. These data provided new insight into the regulation of EBV latency gene expression in different EBV-associated tumors.

DOI： 10.1128/jvi.00739-22

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EBV-associated NK and T-cell lymphoid neoplasms 国際共著 Open Access

Kimura, H; de Leval, L; Cai, QQ; Kim, WS

CURRENT OPINION IN ONCOLOGY   34 巻 ( 5 ) 頁： 422 - 431   2022年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Current Opinion in Oncology  

Purpose of reviewEpstein-Barr virus (EBV)-associated neoplasms derived from natural killer (NK) or T cells comprise a group of clinically and biologically heterogenous disorders affecting children and adults, which are overall rare but more prevalent in Asia and South America. This review focuses on neoplasms presenting in the adulthood, addressing recent genomic discoveries as well as therapeutic developments in these highly aggressive disorders.Recent findingsDistinct molecular subtypes of extranodal NK/T-cell lymphomas (ENKTCLs) have been described, with differences in cell of origin, EBV pattern, genomic alterations, clinical characteristics, response to asparaginase-based therapies and to more recent approaches targeting molecular aberrations of the lymphoma. For the last two decades, progress in the clinical management of ENKTCL was based on L-asapraginase containing combinations and the incoroperation of radiotherapy. A subset of cases with PDL1-2 structural alterations may be more responsive to treatment with immune checkpoint inhibitors. Primary nodal EBV+ lymphomas derived from T or NK cells have distinctive features separating them from both peripheral T-cell lymphoma not otherwise specified and ENKTCL. Treatment algorithms correspond to those for advanced ENKTCL.SummaryWith better understanding of lymphomagenesis, genomic landscape and immunologic aspects of the diseases, future treatment options will include targeted therapies including immune checkpoint inhibitors and novel antibodies.

DOI： 10.1097/CCO.0000000000000889

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

Hara, Y; Watanabe, T; Yoshida, M; Al Masud, HMA; Kato, H; Kondo, T; Suzuki, R; Kurose, S; Uddin, MK; Arata, M; Miyagi, S; Yanagi, Y; Sato, Y; Kimura, H; Murata, T

JOURNAL OF VIROLOGY   96 巻 ( 14 ) 頁： e0051822   2022年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Virology  

Protein-protein interactions (PPIs) are crucial for various biological processes. Epstein-Barr virus (EBV) proteins typically form complexes, regulating the replication and persistence of the viral genome in human cells. However, the role of EBV protein complexes under physiological conditions remains unclear. In this study, we performed comprehensive analyses of EBV PPIs in living cells using the NanoBiT system. We identified 195 PPIs, many of which have not previously been reported. Computational analyses of these PPIs revealed that BLRF2, which is only found in gammaherpesviruses, is a central protein in the structural network of EBV tegument proteins. To characterize the role of BLRF2, we generated two BLRF2 knockout EBV clones using CRISPR/Cas9. BLRF2 knockout significantly decreased the production of infectious virus particles, which was partially restored by exogenous BLRF2 expression. In addition, self-association of BLRF2 protein was found, and mutation of the residues crucial for the self-association affected stability of the protein. Our data imply that BLRF2 is a tegument network hub that plays important roles in progeny virion maturation.

DOI： 10.1128/jvi.00518-22

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

Suzuki, T; Sato, Y; Okuno, Y; Goshima, F; Mikami, T; Umeda, M; Murata, T; Watanabe, T; Watashi, K; Wakita, T; Kitagawa, H; Kimura, H

COMMUNICATIONS BIOLOGY   5 巻 ( 1 ) 頁： 694   2022年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Communications Biology  

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that causes various diseases in humans, ranging from common mucocutaneous lesions to severe life-threatening encephalitis. However, our understanding of the interaction between HSV-1 and human host factors remains incomplete. Here, to identify the host factors for HSV-1 infection, we performed a human genome-wide CRISPR screen using near-haploid HAP1 cells, in which gene knockout (KO) could be efficiently achieved. Along with several already known host factors, we identified 3′-phosphoadenosine 5′-phosphosulfate synthase 1 (PAPSS1) as a host factor for HSV-1 infection. The KO of PAPSS1 in HAP1 cells reduced heparan sulfate (HepS) expression, consequently diminishing the binding of HSV-1 and several other HepS-dependent viruses (such as HSV-2, hepatitis B virus, and a human seasonal coronavirus). Hence, our findings provide further insights into the host factor requirements for HSV-1 infection and HepS biosynthesis.

DOI： 10.1038/s42003-022-03581-9

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