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HASEGAWA Tadao

    Graduate School of Medical Sciences Department of Bacteriology　Professor
Contact： tadaohmed.nagoya-cu.ac.jp
Last Updated :2024/04/24

Researcher Information

URL

J-Global ID

Research Interests

  • 病原細菌   

Research Areas

  • Life sciences / Bacteriology

Academic & Professional Experience

  • 2005- 名古屋市立大学大学院医学研究科細菌学分野 教授
  • 2000-2005 名古屋大学大学院医学系研究科 分子病原細菌学 助教授
  • 1995-2000 国立療養所中部病院長寿医療研究センター老化機構研究部 室長

Education

  • 1987/04 - 1991/03  Nagoya University  Graduate School of Medicine  内科学第一
  • 1979/04 - 1985/03  Nagoya University  医学部  医学科

Association Memberships

  • 日本臨床微生物学会   日本感染症学会   日本細菌学会   

Published Papers

MISC

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2026/03 
    Author : 脇本 寛子; 矢野 久子; 長谷川 忠男; 佐藤 剛
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2024/03 
    Author : 長谷川 忠男; 立野 一郎
     
    A群レンサ球菌は、古くから咽頭炎などの原因菌として知られていたが、1990年前後より再興感染症としての劇症型感染症の起因菌（人喰いバクテリア）となることが報告された。病原性発揮には毒素蛋白質の質的、量的変化が重要な役割を果たしているが、発現制御については未知の部分が多い。今回の研究ではゲノム情報から数多く推定される機能未知の転写調節を司ると考えられる因子の機能を明らかにすることにより、未知の発現制御の解明に取り組んでいる。 1.転写調節遺伝子ノックアウト株の樹立ー劇症型感染症患者由来株である10-85のゲノム情報から転写因子と推定されているもの、仮想蛋白質とされているものでより詳細な検討で転写調節に関与することが考えられる遺伝子をすべてpick upした。それらの遺伝子の網羅的なノックアウト株の樹立を試み、約40種類のノックアウト株を樹立した。 2.蛋白質分解酵素活性の解析ー樹立したノックアウト株について産生する培養上清中のSpeB蛋白質分解酵素をSDS-PAGEにより解析した。またスキムミルク含有BHI培地で培養することにより蛋白質分解酵素活性を検討した。これらの解析により6遺伝子がSpeBの発現の減弱に関与した。そのうち4種はスキムミルク培地においても活性が減弱したが、2種は変化が認められなかった。 3.DNA分解酵素活性の解析ーDNA培地を用いてDNA分解酵素活性を検討した。2種のノックアウト株において活性の減弱を認めた。これらはそれぞれCtsR familyとGntR familyに属すストレス応答転写調節因子であった。またこれらの2種は先に述べたSpeB発現の減少にも関与し、種々の毒素蛋白質発現に関与する重要な発現調節因子であることが示唆された。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2018/04 -2023/03 
    Author : 脇本 寛子; 矢野 久子; 長谷川 忠男; 佐藤 剛
     
    本研究は，新生児GBS感染症予防のために，新生児GBS感染症の発症要因を明らかにすることおよび新生児敗血症髄膜炎発症GBS株と非発症GBS株の微生物学的な異同を明らかにすること（第一研究），GBS保菌妊産褥婦への予防対策とケアを明らかにすること（第二研究）を目的としている． 今年度は，第一研究を優先して実施した．第一研究は，多施設における早発型GBS感染症および遅発型GBS感染症の発症状況と発症頻度を明らかにすることを継続して実施した．細菌学的解析は，血清型，薬剤感受性，MLST型，CovR/S変異を解析した．今年度は，新生児GBS感染症5症例（早発型0例，遅発型5例：確定例5例，疑い例0例）の情報収集を行い，研究対象者から検出されたGBS菌株7株を収集した．薬剤感受性は，penicillin系抗菌薬に耐性を示した株はなく，AZM，EM，CLDM，LVFXの薬剤に耐性を示した菌株もなかった．血清型はIa型3株，III型3株，IV型1株であった．現在までに得られた49株において，型別は抗血清法に追加してPCR法による型別を行い，型別を確定した．今年度の特筆すべき成果として，発症例は全て遅発型の確定例であったことである．全妊婦にスクリーニングを実施し，分娩時にGBS保菌妊婦にpenicillin系抗菌薬を予防投与することは，早発型GBS感染症予防に有用であるが，遅発型の予防には至っていない．遅発型GBS感染症の発症要因を詳細に検討しているところである．また，今年度，一昨年度と複数の施設でIV型のGBSが検出され，発症状況と細菌学的解析を併せて解析しているところである．第二研究は，新生児GBS感染症予防のためのGBS保菌妊産褥婦へのケアについて明らかにし，今後の方策について方向性を決定し，準備を進めた．
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2018/04 -2023/03 
    Author : 井坂 雅徳; 長谷川 忠男; 前山 順一; 立野 一郎; 青山 峰芳; 矢木 宏和
     
    A群連鎖球菌は、咽頭炎や猩紅熱を引き起こす原因菌である。劇症型への機序について様々な研究報告が出ているが、一向に完全解明に至っていない。そこで、劇症型が発症するにはA群連鎖球菌がヒトへ感染後、変化するための何らかの情報を受け取らなければならないと考えた。ここで外界情報を受け取る二成分制御因子の研究が進んでいる、Streptococcus mutansに着目した。A群連鎖球菌と同属のこの細菌は、乳酸、酪酸を産生し、歯にバイオフィルムを形成して虫歯を増悪させる。この細菌の二成分制御因子は酸感受とバイオフィルム形成に関与する。同様の仕組みがA群連鎖球菌に存在するかを調べると、A群連鎖球菌の二成分制御因子の一つであるspy1588遺伝子欠損株は、バイオフィルム産生低下、酸抵抗性の低下を示した。我々は、酸を感受する二成分制御因子と、それに関連する遺伝子群に変異が劇症型に生じていると考え、研究を現在進めている。 昨年度にSPY1588部分ペプチド発現用のpETベクターの作製と、コンピテントセル大腸菌の様々な組み合わせ、および精製法の改良を行った。最終結果として、pET32aベクターにSPY1588のインサートを組み込み、Rosetta Gami2(DE3)にそのベクターを導入した株が、目的産物をIPTGの誘導により強力に発現することが出来た。そしてこの後の目的産物の精製に困難を極めていたが、IPTG誘導後の大腸菌を超音波破砕と界面活性剤を使い分けて遠心分離処理を施すと、目的タンパク質の可溶化が可能になることが明らかとなった。この精製法の確立で、目的タンパク質の精製度が良くなり、タンパク質結晶化に実施するに値する目的産物を得ることが可能となった。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2015/04 -2020/03 
    Author : Tatsuno Ichiro
     
    Streptococcus pyogenes is a causative agent of streptococcal toxic shock syndrome (STSS). Recently, we showed that the regions encoding the SalR-SalK, a two-component regulatory system, were deleted in some emm 1-type isolates (named as “novel-type”). In this study, the two novel “STSS” isolates 10-85 and 11-171 were more virulent than the two novel “non-STSS” isolates 11O-2 and 11T-3 when examined using a mouse model of invasive infection. Genome sequencing experiments using the three strains 10-85, 11-171, and 11O-2 detected only one single nucleotide polymorphism that causes a non-synonymous mutation in fabT encoding a transcriptional regulator in strain 11O-2. Loss of fabT reduced the high level of virulence observed in the STSS isolates to that in the non-STSS isolates, and introduction of an intact fabT compensated the lower virulence of 11O-2, suggesting that the mutation in fabT is involved in the differential virulence among the novel-type clinical isolates.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2016/04 -2019/03 
    Author : isobe ken-ichi
     
    metabolic syndrome represent serious in Japan. We found that aged GADD34 -deficient mice showed fatty liver.We examined the effects of GADD34 on natural life span by using GADD34-deficient mice. We observed that with age GADD34-deficient mice become obese, developing fatty liver followed by liver cirrhosis, hepatocellular carcinoma and insulin resistance. During these studies, we found that nutrients in the foods were important to induce fatty liver. Feeding of sugar, glucose or fructose only diet induced strong nonalcoholic fatty liver disease only in 2 weeks.. High fats (60% fat) without choline diet also induced fatty liver in 2 weeks. For more than one year feeding of adult C57BL/6 female mice egg-only diet did not induce fatty liver. Adding boiled eggs or law egg yolk to sugar, glucose or fructose or only diet or colline deficient diet strongly suppressed fatty liver.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2019/03 
    Author : WAKIMOTO HIROKO; SUZUKI satoshi; WAKIMOTO yukio
     
    The subjects were children who developed early-onset GBS disease (EOGBSD) or late-onset GBS disease (LOGBSD) and their mothers from 5 institutes between 2007 and 2016. There were 14 cases of EOGBSD and 17 cases of LOGBSD, inborn cases were 4 cases both EOGBSD and LOGBSD, with estimated incidence of 0.10 per 1,000 live births for both EOGBSD and LOGBSD. We divided the study period into two parts; the period before (period I: 2007-2008) and after (period II: 2009-2016) issue of the guideline for prevention of vertical transmission in Japan. The incidence of EOGBS was significantly lower in period II (0.03 per 1,000 births) than in period I (0.42 per 1,000 births) (p = 0.02). The incidence of EOGBSD would further decline with proper timing of GBS screening, sampling site, culture method, and appropriate antibacterial prophylaxis for pregnant GBS carriers.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2014/04 -2019/03 
    Author : Isaka Masanori
     
    Group A streptococci cause the severe invasive disease, but the mechanism is unknown.The two-component regulatory system receives external stimuli and transmits a signal to inside the cells.Streptococcus pyogenes produces biofilm production.Biofilm is one of the virulence factors, and its production is produced by external stimuli. Streptococcus mutans has been thought to be associated with dental caries, its the two-component sensor protein recognizes the acid produced by sugar fermentation.
  • ファージ由来DNAに注目したA群レンサ球菌のマクロライド耐性機構と病原性の解明
    日本学術振興会：基盤研究(C)
    Date (from‐to) : 2016/04 -2019/03 
    Author : 長谷川 忠男
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2017/03 
    Author : isobe ken-ichi
     
    We intended to analyze age-related disease from the points of ER stresses and immune responses. Acrolein, which is abundant in cigarette smoke, and cooking emission, plays a major role in COPD . Acrolein induced the expression of GADD34 and acute inflammation in airways, which followed COPD. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. We examine the effects of GADD34 on natural life span by using GADD34-deficient mice. We found that with age GADD34-deficient mice become obese, developing fatty liver followed by liver cirrhosis, hepatocellular carcinoma, and insulin resistance. GADD34 suppresses insulin signaling in young mice. However, by aging macrophages in fat tissues work to induce insulin resistance. We succeeded to differentiate to various tissue cells from iPSCs established from aged mice, which may repair damaged tissues by age-related diseases.
  • A群レンサ球菌における二成分制御系センサー蛋白質のネットワークの解明に関する研究
    日本学術振興会：基盤研究(C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : Tadao Hasegawa; 立野一郎; 井坂雅徳
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2011 -2013 
    Author : MINAMI MASAAKI; HASEGAWA Tadao
     
    e investigated whether Japanese traditional medicine, Hainosankyuto affect the cure of MRSA severe infection disease. In two-dimensional electrophoresis analysis, we found that the amount of extra virulent proteins from MRSA in LB with Hainosankyuto were decreased compared to those in LB. We also found the significant improvement of survival rate and cutaneous ulcer formation in Hainosankyuto-treated mouse after MRSA subcutaneous infection. Furthermore we confirmed that the phagocytosis ability of mouse peritoneal macrophage treated with Hainosankyuto was significantly greater than that without it. We suggested that Hainosankyuto is the candidate of novel anti- MRSA infectious treatment.
  • A群レンサ球菌における糖輸送系蛋白質発現制御因子と病原性に関する研究
    日本学術振興会：基盤研究(C)
    Date (from‐to) : 2009/04 -2012/03 
    Author : 長谷川 忠男
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2007 -2008 
    Author : TATSUNO Ichiro; HASEGAWA Tadao; ISAKA Masanori
     
    A群連鎖球菌は近年(1900年以降)劇症型感染症の起因菌となる例が報告されるようになった。これは、本菌が新たな外来病原因子を獲得したためである可能性が指摘されている。本菌によって菌体外に分泌されるNAD-glycohydrolase(NADase or Nga)はその候補の一つである。そこで本研究では、当初の計画通り実験を行い、(1)マウスモデルを用いてnga遺伝子欠損株が劇症型感染症に関する病原性が低下する、(2)酵素活性に重要なアミノ酸残基(330番目)の同定、(3)本酵素活性を阻害するタンパク質を使用することによる本菌病原性の抑制、などの研究成果を得た。
  • A群レンサ球菌毒素蛋白質発現機構の網羅的解明とその制御に関する研究
    日本学術振興会：基盤研究(C)
    Date (from‐to) : 2004/04 -2006/03 
    Author : 長谷川 忠男
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2002 -2004 
    Author : OHTA Michio; HASEGAWA Tadao; TORII Keizo
     
    We analyzed the mechanisms of the expression of exoproteins such as toxins and enzymes in Staphylococcus aureus and Streptococcus pyogenes. We performed comprehensive analyses of exoproteins of these bacteria by two dimensional gel electrophoresis (2-DE) and LC/MS/MS and constructed 2-DE maps. We detected putative genes that affect the expression of exoproteins in genome databases and constructed knockout mutants of these genes and analyzed the functions of these genes. The results were as follows. Molecular epidemiological study for 23 exotoxin genes revealed that most Japanese MRSA strains were TSST-1,SEC3 and egc locus-positive, suggesting that these MRSA are very clonal. The differences of the expressed amount of each toxin were analyzed by 2-DE. We found that the expression of TSST-1 was very high in the strains that caused neonatal toxic shock-like exanthematous disease. The production of TSST-1 was suppressed by glucose-mediated catabolite repression. The difference of agr locus was not observed in theses trains. We found that the expression of Sic protein was regulated by mga, a global regulator of S.pyogenes, since the production of Sic was reduced in an mga-knockout mutant, and that other several exoproteins were also regulated by mga. It is very likely that the specific secretion machineries are involved in the expression of exoproteins in S.aureus and S.pyogenes, respectively. We found a tat-like gene similar to tat gene of Escherichia coli in the genome of S.aureus. We constructed tat-knockout mutants and found that the expression of several exoproteins were reduced in these mutants, suggesting that this tat-like gene is functional in S.aureus. Interestingly, fat-like gene was found in S.intermedius but not in other coagulase-negative staphylococci. These results suggested that Tat was involved in the virulence of staphylococci. We detected four signal peptidase I (SPaseI)-like genes in the genome of S.pyogenes and constructed knockout mutants of sipC and spi genes. A sipC mutant reduced the expression of 54 exoproteins and a spi mutant reduced the expression of 36 exoproteins. We found preferential expression of some exoproteins in each mutant.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2000 -2002 
    Author : OHTA Michio; IINUMA Yoshitsugu; TORII Keizo; HASEGAWA Tadao; YAMASINO Takafumi
     
    Discrimination of each strain of bacteria such as Staphylococcus aureus and group A streptococcus (GAS) is helpful for tracing a pathogenic strain and prevention of nosocomial infections. Although DNA-based typings have been generally used as epidemiological methods for discrimination, we developed two dimensional electrophoretic (2-DE) analysis of exoproteins secreted from bacteria as a new epidemiological method and we found that this method was well applicable for the discrimination of S.aureus and GAS strains. The conditions of culture, growth and extraction of exoproteins were identified to have reproducible results. The major results of this study were as follows ; the best condition was that exoproteins were extracted from early stationary culture with TCA and were quickly applied on 2-DE ; high degree of variety was observed in the 2-DE patterns of exoproteins in S.aureus and GAS ; spots of more than 100 exoproteins of S.aureus and 20 of GAS were identified by the determination of N-terminal amino acid sequences ; a specific spot pattern was identified for each coagulase type of MRSA and variation of the spots of super antigens were observed among the strains belonging to the same coagulase type ; a correlation was observed between the spot patterns and M antigen types in GAS strains ; the MRSA strains that caused NTED and SSSS showed unique toxin production patterns, respectively, observed by 2-DE ; we have accumulated 2-DE patterns of more number of strains that would be helpful for the construction of a 2-DE database of exoproteins.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1999 -2000 
    Author : OHTA Michio; YAMASHINO Takafumi; HASEGAWA Tadao
     
    Streptococcus pyogenes secretes a variety of toxins and enzymes. These proteins, as well as surface proteins, are considered as important virulence factors. We extracted whole exoproteins of the clinical isolates of S.pyogenes from the patients who suffered toxic shock-like syndrome (TSLS) and characterized them by the two-dimensional gel electrophoresis technique. The protein expression patterns from many of the clinical isolates of the same M serotype were almost same, suggesting that the clinical features caused by them were similar. However some clinical isolates of the same M type which showed different clinical features had different protein expression patterns. We sequenced N-terminal amino acids of the proteins isolated by the two-dimensional gel electrophoresis and detected SpeB, SpeF and streptolysin O by using DNA data bank. In addition, we detected several unreported proteins which we considered as virulence factors. We have already cloned four of them. We performed the DNA sequencing, made recombinant proteins and found that they had DNase activities. We detected SpeF, which is considered to play an important roles in adult respiratory distress syndrome (ARDS), as fairly large amounts in S.pyogenes of both M1 and M3 serotypes. However, we found that SpeF had different N-terminal amino acid and different isoelectricity. We are now studying the biological significance of different SpeF spots.

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  • 論文査読
    Date (from-to) : 2006/10-Today
    Role : Others
    Sponser, Organizer, Publisher  : その他
    ― 学術雑誌投稿論文の査読
  • 愛知県衛生研究所運営委員会委員
    Date (from-to) : 2006/08-Today
    Role : Advisor
    Category : Others
    Sponser, Organizer, Publisher  : 行政
    愛知県衛生研究所 愛知県衛生研究所運営委員会への出席
  • 名古屋市衛生研究所調査研究協議会委員
    Date (from-to) : 2006/08-2018/08
    Role : Advisor
    Sponser, Organizer, Publisher  : 行政
    名古屋市衛生研究所 調査研究事項の審議
  • 名古屋市立大学 医・薬・看連携研究事業にて講演会を実施
    Date (from-to) : 2011/08-2013/03
    Role : Planner
    Sponser, Organizer, Publisher  : 名古屋市立大学
    名古屋市立大学 介護施設従事者を対象に講演会等の実施

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