生体防御部：概要
生体防御部は病理科、免疫科、動物実験科の３科があり、さらに主任研究員で構成されています。病理科、免疫科では、結核の感染、発症、再発などに関わる生体側の現象を遺伝子、細胞レベルで分析・統合し、抗酸菌症の分子病態を理解して、その知見を対策に役立てることを目標としています。動物実験科は実験動物を用いる各種基礎研究の支援業務を行っています。主任研究員は新抗結核薬・化学療法プロジェクトの責任者として、新規抗酸菌薬開発と結核併用化学療法に関する薬理学的解析・研究を行なっています。
途上国とのゲノム臨床疫学共同研究
10年以上前からハノイ市肺病院を中心としたベトナムの医療機関と国際共同研究を行っています。バックマイ病院にある医学共同研究センターを拠点に、結核症の感染、発症、再発に関わる宿主遺伝子、免疫病態、臨床疫学因子の解析、菌と宿主因子の相互関連に関する検討など幅広い研究を実施しています。特に多剤耐性結核対策につながる成果を目指しています。
ハノイ市肺病院、ハノイ市各郡の結核センターの代表者に対して、結核の臨床疫学指標、血液中の免疫代謝指標と治療反応性、再発率の関係、治療脱落の問題など、共同研究の進捗状況を報告している。
疾患感受性遺伝子と分子病態の研究
気道粘膜防御因子群の遺伝子多型の機能的意義について検討しています。我々はヒト第６染色体上に新規のムチン遺伝子を同定したほか、βデフェンシン類、インターフェロン誘導性抗ウイルス分子など、ヒト気道上皮細胞における遺伝子多型の機能的意義を明らかにして、広く慢性気道炎症性疾患の病態に迫る研究を行なっています。
第６染色体上の慢性気道炎症性疾患感受性遺伝子候補領域内に同定された新規ムチン・ムチン様遺伝子(PBMUCL1, PBMUCL2) 。遺伝子多型と気道粘膜防御との関連が推測される。
結核菌の細胞内寄生戦略を解明する研究
結核菌はマクロファージに貪食されても、その殺菌分解機構を回避して、貪食したマクロファージ内で増殖することができる細胞内寄生性細菌です。私たちは、結核菌感染マクロファージにおける小胞輸送を明らかにすることによって、結核菌のユニークな細胞内寄生戦略を解明する研究を行っています。特に、結核菌によるファゴリソソーム阻害機構とオートファジー誘導阻害機構に関して、さまざまな新知見を蓄積しています。
マクロファージ感染結核菌へのオートファゴソーム形成。Coronin-1aは宿主細胞のアクチン結合タンパク質である。Coronin-1aをノックダウンしたマクロファージに結核菌（青）を感染させると、結核菌はオートファジーの標的となり、オートファゴソーム形成（緑、赤）が行われる。
動物モデルを用いた結核研究
結核菌は、ヒトだけでなく動物でも感染が成立します。しかし、動物によって結核菌に対する感受性は異なり、一般的な実験動物であるマウスでの病理組織像はヒト結核とは異なることが報告されています。近年、ヒト活動性結核を反映していると考えられる結核マウスモデルが開発されています。このモデルマウスを用いて、結核病変形成に関わる宿主・菌因子の研究を行っています。
動物研究棟ABSL3実験室内の様子
2013年- 業績（欧文）
Noguchi S, Hamano E, Matsushita I, Hijikata M, Ito H, Nagase T, Keicho N. Differential effects of a common splice site polymorphism on the generation of OAS1 variants in human bronchial epithelial cells. Hum Immunol 74 (3): 395-401, 2013.
Noguchi S, Hijikata M, Hamano E, Matsushita I, Ito H, Ohashi J, Nagase T, Keicho N. MxA transcripts with distinct first exons and modulation of gene expression levels by single-nucleotide polymorphisms in human bronchial epithelial cells. Immunogenetics 65 (2): 107-14, 2013.
Pitabut N, Sakurada S, Tanaka T, Ridruechai C, Tanuma J, Aoki T, Kantipong P, Piyaworawong S, Kobayashi N, Dhepakson P, Yanai H, Yamada N, Oka S, Okada M, Khusmith S, Keicho N. Potential function of granulysin, other related effector molecules and lymphocyte subsets in patients with TB and HIV/TB coinfection. Int J Med Sci 10 (8): 1003-1014, 2013.
Hang NT, Maeda S, Lien LT, Thuong PH, Hung NV, Thuy TB, Nanri A, Mizoue T, Hoang NP, Cuong VC, Ngoc KT, Sakurada S, Endo H, Keicho N. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors. PLoS One 8 (8): e71867, 2013.
Hung NV, Ando H, Thuy TT, Kuwahara T, Hang NT, Sakurada S, Thuong PH, Lien LT, Keicho N. Clonal expansion of Mycobacterium tuberculosis isolates and coexisting drug resistance in patients newly diagnosed with pulmonary tuberculosis in Hanoi, Vietnam. BMC Res Notes 6:444, 2013.
Hang NT, Matsushita I, Shimbo T, Hong LT, Tam DB, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Endo H, Keicho N. Association between tuberculosis recurrence and interferon-γ response during treatment. J Infect 69 (6): 616-626, 2014.
Hijikata M, Matsushita I, Hang NT, Maeda S, Thuong PH, Tam DB, Shimbo T, Sakurada S, Cuong VC, Lien LT, Keicho N. Age-dependent association of mannose-binding lectin polymorphisms with the development of pulmonary tuberculosis in Viet Nam. Hum Immunol 75 (8): 840-846, 2014.
Maeda S, Hang NT, Lien LT, Thuong PH, Hung NV, Hoang NP, Cuong VC, Hijikata M, Sakurada S, Keicho N. Mycobacterium tuberculosis strains spreading in Hanoi, Vietnam: Beijing sublineages, genotypes, drug susceptibility patterns, and host factors. Tuberculosis 94 (6): 649-656, 2014.
Hang NT, Maeda S, Keicho N, Thuong PH, Endo H. Sublineages of Mycobacterium tuberculosis Beijing genotype strains and unfavorable outcomes of anti-tuberculosis treatment. Tuberculosis 95 (3): 336-342, 2015.
Jeong S, Patel N, Edlund CK, Hartiala J, Hazelett DJ, Itakura T, Wu PC, Avery RL, Davis JL, Flynn HW, Lalwani G, Puliafito CA, Wafapoor H, Hijikata M, Keicho N, Gao X, Argüeso P, Allayee H, Coetzee GA, Pletcher MT, Conti DV, Schwartz SG, Eaton AM, Fini ME. Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Invest Ophthalmol Vis Sci 56 (4): 2737-2748, 2015.
Matsushita I, Hang NT, Hong LT, Tam DB, Lien LT, Thuong PH, Cuong VC, Hijikata M, Kobayashi N, Sakurada S, Higuchi K, Harada N, Keicho N. Dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon-gamma response at the time of diagnosis. Int J Infect Dis 40:39-44, 2015.
Yatagai Y, Hirota T, Sakamoto T, Yamada H, Masuko H, Kaneko Y, Iijima H, Naito T, Noguchi E, Tamari M, Kubo M, Takahashi A, Konno S, Makita H, Nishimura M, Hijikata M, Keicho N, Homma S, Taguchi Y, Azuma A, Kudoh S, Hizawa N. Variants nearby the HLA complex group 22 gene confer increased susceptibility to late-onset asthma in Japanese populations. J Allergy Clin Immunol 138 (1): 281-283.e13, 2016.
Nakauchi A, Wong JH, Mahasirimongkol S, Yanai H, Yuliwulandari R, Mabuchi A, Liu X, Mushiroda T, Wattanapokayakit S, Miyagawa T, Keicho N, Tokunaga K. Identification of ITPA as a susceptibility gene to young-onset Tuberculosis on Chromosome 20. Human Genome Variation 3:15067, 2016.
Hijikata M, Matsushita I, Hang NT, Thuong PH, Tam DB, Maeda S, Sakurada S, Cuong VC, Lien LT, Keicho N. Influence of the polymorphism of the DUSP14 gene on the expression of immune-related genes and development of pulmonary tuberculosis. Genes and Immunity 17 (4): 207-212, 2016.
Thuong PH, Tam DB, Sakurada S, Hang NT, Hijikata M, Hong LT, Ngoc PT, Anh PT, Cuong VC, Matsushita I, Lien LT and Keicho N. Circulating granulysin levels in healthcare workers and latent tuberculosis infection estimated using interferon-gamma release assays. BMC Infectious Diseases 16 (1): 580, 2016.
Wada T, Hijikata M, Maeda S, Hang NT, Thuong PH, Hoang NP, Hung NV, Keicho N. Complete genome sequences of three representative Mycobacterium tuberculosis Beijing family strains belonging to distinct genotype clusters in Hanoi, Vietnam, during 2007–2009. Genome Announc 5 (27):2017. pii: e00510-17.
Wada T, Hijikata M, Maeda S, Hang NT, Thuong PH, Hoang NP, Hung NV, Keicho N. Complete genome sequence of a Mycobacterium tuberculosis strain belonging to the EAI family in the Indo-Oceanic lineage, isolated in Hanoi, Vietnam. Genome Announc 5 (24):2017. pii: e00509-17.
Hijikata M, Keicho N, Duc LV, Maeda S, Hang NTL, Matsushita I, Kato S. Spoligotyping and whole-genome sequencing analysis of lineage 1 strains of Mycobacterium tuberculosis in Da Nang, Vietnam. PLoS One 12 (10): e0186800, 2017.
Morimoto K, Hijikata M, Zariwala MA, Nykamp K, Inaba A, Guo TC, Yamada H, Truty R, Sasaki Y, Ohta K, Kudoh S, Leigh MW, Knowles MR, Keicho N. Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients. Mol Genet Genomic Med. 00:e838, 2019.
Maeda S, Hijikata M, Hang NTL, Thuong PH, Huan HV, Hoang NP, Hung NV, Cuong VC, Miyabayashi A, Seto S, Keicho N. Genotyping of Mycobacterium tuberculosis spreading in Hanoi, Vietnam using conventional and whole genome sequencing methods. Infect Genet Evol. 78:104107, 2020.
Keicho N, Hijikata M, Morimoto K, Homma S, Taguchi Y, Azuma A, Kudoh S. Primary ciliary dyskinesia caused by a large homozygous deletion including exons 1-4 of DRC1 in Japanese patients with recurrent sinopulmonary infection. Mol Genet Genomic Med. 00:e1033, 2019.
Hang NTL, Hijikata M, Maeda S, Thuong PH, Ohashi J, Van Huan H, Hoang NP, Miyabayashi A, Cuong VC, Seto S, Van Hung N, Keicho N. Whole genome sequencing, analyses of drug resistance-conferring mutations, and correlation with transmission of Mycobacterium tuberculosis carrying katG-S315T in Hanoi, Vietnam. Sci Rep 9(1):15354, 2019.
Seto S, Morimoto K, Yoshida T, Hiramatsu M, Hijikata M, Nagata T, Kikuchi F, Shiraishi Y, Kurashima A, Keicho N. Proteomic profiling reveals the architecture of granulomatous lesions caused by tuberculosis and Mycobacterium avium complex lung disease. Front Microbiol 10: 3081, 2020.
Hang NTL, Hijikata M, Maeda S, Miyabayashi A, Wakabayashi K, Seto S, Diem NTK, Yen NTT, Duc LV, Thuong PH, Huan HV, Hoang NP, Mitarai S, Keicho N, Kato S. Phenotypic and genotypic features of the Mycobacterium tuberculosis lineage 1 subgroup in central Vietnam. Sci Rep 11(1):13609, 2021.
Furuuchi K, Seto S, Nakamura H, Hikichi H, Miyabayashi A, Wakabayashi K, Mizuno K, Oka T, Morimoto K, Hijikata M, Keicho N. Novel Screening System of Virulent Strains for the Establishment of a Mycobacterium avium Complex Lung Disease Mouse Model Using Whole-Genome Sequencing. Microbiol Spectr. e0045122, 2022.
Seto S, Nakamura H, Guo TC, Hikichi H, Wakabayashi K, Miyabayashi A, Nagata T, Hijikata M, Keicho N. Spatial multiomic profiling reveals the novel polarization of foamy macrophages within necrotic granulomatous lesions developed in lungs of C3HeB/FeJ mice infected with Mycobacterium tuberculosis. Front Cell Infect Microbiol 12:968543, 2022.
Hikichi H, Seto S, Wakabayashi K, Hijikata M, Keicho N. Transcription factor MAFB controls type I and II interferon response-mediated host immunity in Mycobacterium tuberculosis-infected macrophages. Front Microbiol 13:962306, 2022.
Hijikata M, Morimoto K, Takekoshi D, Shimoda M, Wakabayashi K, Miyabayashi A, Guo TC, Yamada H, Keicho N. Analysis of Aberrant Splicing Events and Gene Expression Outliers in Primary Ciliary Dyskinesia. Am J Respir Cell Mol Biol 68(6):702-705, 2023.
Keicho N, Morimoto K, Hijikata M. The challenge of diagnosing primary ciliary dyskinesia: a commentary on various causative genes and their pathogenic variants. J Hum Genet 68:571-575, 2023.
Hang NTL, Hijikata M, Maeda S, Thuong PH, Huan HV, Hoang NP, Tam DB, Anh PT, Huyen NT, Cuong VC, Kobayashi N, Wakabayashi K, Miyabayashi A, Seto S, Keicho N. Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance-conferring mutations. Front Microbiol 14:1187390, 2023.
Ito M, Morimoto K, Ohfuji T, Miyabayashi A, Wakabayashi K, Yamada H, Hijikata M, Keicho N. FOXJ1 Variants Causing Primary Ciliary Dyskinesia with Hydrocephalus: A Case Report from Japan. Intern Med. 2023 Oct 6. doi:10.2169/internalmedicine.2565-23.
Keicho N, Hijikata M, Miyabayashi A, Wakabayashi K, Yamada H, Ito M, Morimoto K. Impact of primary ciliary dyskinesia: Beyond sinobronchial syndrome in Japan. Respir Investig. 2024 Jan;62(1):179-186.
Ito M, Morimoto K, Saotome M, Miyabayashi A, Wakabayashi K, Yamada H, Hijikata M, Keicho N, Ohta K. Primary Ciliary Dyskinesia Caused by Homozygous DNAAF1 Mutations Resulting from a Consanguineous Marriage: A Case Report from Japan. Intern Med. 2024 Mar 4. doi: 10.2169/internalmedicine.3263-23.
Horita Y, Doi N. Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein．Antimicrob Agents Chemother 58 (6): 3168-3176, 2014.
Horita Y, Maeda S, Kazumi Y, Doi N. In vitro susceptibility of Mycobacterium tuberculosis isolates to an oral carbapenem alone or in combination with -lactamase inhibitors．Antimicrob Agents Chemother 58 (11): 7010-7014, 2014.
Disratthakit A, Prammananan T, Tribuddharat C, Thaipisuttikul I, Doi N, Leechawengwongs M, Chaiprasert A. Role of gyrB Mutation in Pre-extensively and Extensively Drug-Resistant Tuberculosis in Thai Clinical Isolates. Antimicrob Agents Chemother 60 (9): 5188-5197, 2016.
Horita Y, Alsultan A, Kwara A, Antwi S, Enimil A, Ortsin A, Dompreh A, Yang H, Wiesner L, Peloquin CA. Evaluation of the adequacy of WHO revised dosages of the first-line antituberculosis drugs in children with tuberculosis using population pharmacokinetic modeling and simulations. Antimicrob Agents Chemother. 62(9), 2018. pii: e00008-18.