研究者業績
基本情報
研究キーワード
2研究分野
1経歴
1-
2014年4月 - 現在
受賞
7-
2020年10月
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2020年2月
論文
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Respirology case reports 12(7) e01433 2024年7月Schizophyllum commune is the third most common causative fungus of allergic bronchopulmonary mycosis(ABPM). Two-thirds of ABPM caused by S. commune can be positive for Aspergillus fumigatus-specific IgE, which can be difficult to diagnose. Our patient presented to our hospital with wet cough for 3 months and chest pain for 3 days. Blood tests showed IgE 1522 IU/mL, eosinophils 688/mm3, A. fumigatus -specific IgE 2.24 UA/mL, and chest computed tomography showed high-attenuation mucus. Bronchoscopy showed mucus plugs and speculum examination showed filamentous fungi, but various culture tests did not detect A. fumigatus, Asp f 1-specific IgE was negative, and S. commune was detected in the culture of bronchial washing. Since he was positive for S. commune-specific IgE and IgG, he diagnosed ABPM caused by S. commune. These findings demonstrate the importance of identifying the causative fungus in ABPM by detailed examination.
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Journal of Infection and Chemotherapy 2024年7月Pediatric myelodysplasia syndrome is often characterized by hypoplastic bone marrow morphology and predisposition to infection. Invasive aspergillosis during hematopoietic stem cell transplantation poses a significant threat and often requires voriconazole (VRCZ) therapy. However, difficulties in achieving appropriate VRCZ blood levels due to drug interactions have prompted the exploration of alternative treatments, such as isavuconazole (ISCZ). We present the case of a 4-year-old boy with myelodysplasia syndrome who developed multiple abscesses, including a brain abscess caused by Aspergillus fumigatus, and was successfully treated with ISCZ. Despite initial treatment with liposomal amphotericin B and VRCZ, the patient's condition deteriorated. Transitioning to ISCZ treatment resulted in significant clinical improvement, resolution of the abscesses, and reduced antigen levels. Although ISCZ induced hepatic enzyme elevation, supportive care improved without discontinuation of treatment. This case highlights the potential of ISCZ in cases of pediatric invasive aspergillosis where traditional therapies fail, underscoring the need for further research and formulation development to optimize its use in this population. As more cases accumulate, ISCZ may become a promising option for treating severe invasive aspergillosis in pediatric patients undergoing hematopoietic stem cell transplantation.
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Journal of fungi (Basel, Switzerland) 10(7) 2024年6月29日BACKGROUND: Approximately 60% of individuals with cystic fibrosis (CF) are affected by Aspergillus fumigatus infection. This condition is correlated with a decline in lung function and is identified as an independent risk factor contributing to hospital admissions among CF patients. This study investigates the dynamic interplay of A. fumigatus within the context of CF patients, tracing its evolution over time, with a specific emphasis on colonization dynamics. METHODS: An analysis was conducted on 83 sequential A. fumigatus isolates derived from sputum samples of six patients receiving care at a renowned CF hospital in Brazil. Employing microsatellite genotyping techniques, alongside an investigation into cyp51A gene mutations, this research sheds light on the genetic variations, colonization, and resistance of A. fumigatus within the CF respiratory environment. RESULTS: Our research findings indicate that CF patients can harbor A. fumigatus strains from the same clonal complexes for prolonged periods. Additionally, we identified that clinical isolates have the potential to spread among patients in the same healthcare facility, evidencing hospital contamination. Two patients who underwent long-term Itraconazole treatment did not show phenotypic resistance. However, one of these patients exhibited mutations in the cyp51A gene, indicating the need to monitor resistance to azoles in these patients colonized for long periods by A. fumigatus. We also observed co-colonization or co-infection involving multiple genotypes in all patients over time. CONCLUSION: This comprehensive examination offers valuable insights into the pathogenesis of A. fumigatus infections in CF patients, potentially shaping future therapeutic strategies and management approaches. This enhanced understanding contributes to our knowledge of A. fumigatus impact on disease progression in individuals with cystic fibrosis. Additionally, the study provides evidence of cross-contamination among patients undergoing treatment at the same hospital.
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American journal of ophthalmology case reports 34 102062-102062 2024年6月PURPOSE: We report a rare case of microbial keratitis caused by Nigrospora oryzae. OBSERVATIONS: A 72-year-old Japanese woman was injured by plant debris and developed oval corneal ulcers and hypopyon in the anterior chamber. After 5 days, she complained of pain, redness, and vision loss in her left eye and was treated with antibacterial eye drops and an ointment (1.5 % levofloxacin hydrate, cefmenoxime hydrochloride, and sterilization and disinfection eye drops; SAN-IODE and ofloxacin ophthalmic ointment). Examination revealed a worsening oval corneal ulcer with Descemet's folds and a faint hypopyon. Considering the infection from soil or plants and the poor response to intensive antibacterial eye drops, topical antifungal eye drops, i.e., 1 % voriconazole eye drops, and 1 % natamycin ointment were applied. Direct microscopy of the corneal scraping with Gram staining was performed and the result was negative. Cultures from corneal scrapings showed the growth of dark colonies after several days. The colony was identified as Nigrospora oryzae by sequencing of the fungal internal transcribed spacer region. Pain and vision loss improved with improvement in corneal ulcers. The antifungal treatment was administered for 37 days. Discontinuation of the eye drops after 1 month did not result in keratitis recurrence. At the final follow-up at 70 days, the best-corrected visual acuity was 20/25, with persistent small corneal opacity. CONCLUSIONS AND IMPORTANCE: Here, we report a case of fungal keratitis caused by Nigrospora oryzae. Microbiological identification of the causes of rare infections is difficult in clinical laboratories, necessitating the use of advanced molecular techniques based on amplification and sequencing of appropriate phylogenetic markers. Nigrospora oryzae responds to topical voriconazole and natamycin.
MISC
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日本内科学会雑誌 103(11) 2674-2679 2014年輸入真菌症の症例数は増加している．特にヒストプラズマ症，コクシジオイデス症の増加が顕著であるが，マルネッフェイ型ペニシリウム症の漸増にも留意すべきである．一般的な深在性真菌症とは異なり，輸入真菌症の原因菌には感染力の極めて強いものが多く，健常な旅行者でも感染し得る．同じ理由から一般医療機関での培養検査は行うべきではない．流行地域からの帰国者，入国者の診察の際には本症を鑑別疾患に挙げる必要がある．
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INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 42 S120-S120 2013年6月
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日本呼吸器学会誌 = Annals of the Japanese Respiratory Society 1(7) 609-613 2012年11月10日
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日本医真菌学会総会プログラム抄録集 51(1) 42-42 2010年9月17日
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EUROPEAN JOURNAL OF HAEMATOLOGY 85(3) 277-277 2010年9月
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日本医真菌学会総会プログラム・抄録集 52 158-158 2008年我々はこれまでに黒色真菌の一種であるStachybotrys chartarum の胞子を経気管的に反復投与したマウスで肺動脈壁の著しい肥厚が形成され、肺高血圧が惹起されることを確認してきた。今回の研究はS. chartarum 以外にも同様の病変を惹起する真菌があるかどうかを検討することを目的とした。被検菌にはAspergillus fumigatus (Af) を5株、Cladosporium cladosporioides (Cc)、Penicillium citrinum (Pc) を各1株ずつ用い、各菌株の胞子懸濁液をマウスに4週間かけて計6回経気管的に反復投与した。投与菌量は1回あたり1×104spores/mouseとし、CcとPcでは1×105及び1×106spores/mouseの投与も試みた。この結果、1×104spores/mouseのAf投与群の一部の株で肺動脈壁の肥厚が確認された。Ccを大量に投与した場合にも同様の病変が形成された。Pcではこのような病変は形成されなかった。いずれも肺内で胞子は発育しなかった。また、肝、腎、脾に病理組織学的変化は認められなかった。現在、株数を増やして更に検討を進めているところである。
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INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE 11(12) 1381-1381 2007年12月
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日本医真菌学会総会プログラム・抄録集 51 131-131 2007年我々はこれまでに黒色真菌Stachybotrys chartarum の胞子を経気管的反復投与したマウスで肺高血圧症が惹起されることを確認してきた。そこで今回は、本病変の形成機序を解明する一助として、本菌胞子のメタノール処理が肺動脈病変形成に及ぼす影響を検討した。S. chartarum （IFM53637）をPDA培地にて25℃で3週間培養した胞子を用いた。この胞子をメタノールまたは蒸留水に浸漬した後、蒸留水で洗浄し、胞子のCFUがそれぞれ0、66であることを確認した。これらの胞子を用いて胞子懸濁液を作製し、1×104 spores/mouse を2週間に3回の頻度で経気管的にddYマウスに反復投与した。投与を計6回行い、投与終了後７日目の肺、肝、腎、脾について病理組織学的検討を行うとともに、臓器重量、右室/(左室＋隔壁)重量比を調べた。その結果、蒸留水に浸漬した胞子を投与した場合では10匹中6匹のマウスで肺動脈壁の肥厚が認められたが、メタノール処理をした胞子を投与した場合にはこのような肺動脈病変は形成されなかった。臓器重量および右室/(左室＋隔壁)重量比に有意差はなかった。以上の結果から、肺動脈病変の形成にはメタノール処理によって胞子から除去される物質が関与する可能性などが考えられた。これらについては現在検討を行っている。
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日本医真菌学会総会プログラム・抄録集 51 65-65 2007年抗がん薬、免疫抑制薬、ステロイド薬の投与などに伴う免疫機能が低下している患者において侵襲性肺アスペルギルス症が増加している。また、環境からしばしば分離されるアスペルギルス属菌は、肺アスペルギローマ、慢性壊死性肺アスペルギルス症、アレルギー性気管支肺アスペルギルス症などの原因菌として、我々の生活を脅かしている。アスペルギルス症の主な原因菌である <I>Aspergillus fumigatus</I> について各種検体中（血液、喀痰、気管支肺胞洗浄液あるいは組織等）での存在を迅速に判定し、アスペルギルス症の診断・治療に役立てる目的で、リアルタイム PCR を応用した迅速定量法を開発した。PCRには、プローブとして Roche 社の Universal prove #115 と#160 を用い、genomic DNA の rDNA 領域を増幅し、蛍光を測定した。ヒト、マウスなどの宿主哺乳類やカビ、酵母、細菌の精製 DNA 標本を用いて調べた結果、プローブ #115 は <I>A. fumigatus</I> に対して高い特異性を示し、同菌のDNAを試験管あたり２胞子から106 胞子相当のレベルまで、直線的に検出することができた。また水溶液に懸濁した胞子をそのまま検出することも可能であった。現在、実験動物から採取した血液中の胞子の数の測定を試みており、これらの結果について報告する。
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日本医真菌学会総会プログラム・抄録集 50 106-106 2006年我々はこれまでに、わが国のハウスダストから分離された黒色真菌Stachybotrys chartarumの胞子を経気管的に反復投与したマウスの肺動脈において中膜および内膜の肥厚による狭窄が惹起され、原発性肺高血圧症に類似した血管病変が生じることを明らかにした。S. chartarumには細胞毒性を有するsatratoxinを含むtrichotheceneを産生する株と、これを産生しない株とがあることが知られている。そこで、本研究ではこれら2株を用いて肺動脈病変形成における相違を検討した。<BR> S. chartarumの菌株は米国の住居から分離されたtrichothecene 産生株（ATCC201211）およびtrichothecene非産生株（ATCC201863）を用いた。各株の胞子懸濁液を2週間に3回ずつ経気管的にddYマウスに反復投与し、計6回の投与終了後７日目の肺およびその他の諸臓器について病理組織学的検討を行った。その結果、trichothecene産生株を反復投与した場合に約40%のマウスに肺動脈壁の肥厚あるいは内腔の狭窄が認められた。一方、trichothecene非産生株では肺動脈病変を有するマウスは認められなかった。このことより、S. chartarumによる肺動脈病変の形成にはtrichotheceneが関わっている可能性が示唆された。
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MEDICAL MYCOLOGY 43 S95-S99 2005年5月Aspergillus fumigatus is known to produce various immunosuppressive mycotoxins including gliotoxin. However, none of these mycotoxins has been confirmed as being directly related to the pathogenesis of aspergilli. Recent studies have made substantial progress in the determination of mycotoxins as virulence factors. Gliotoxin was found to be produced much faster than previously believed under certain culture conditions, such as at 37 degrees C and under high oxygen content, which is close to the environment in the host. Gliotoxin was also found to be detectable in the sera of aspergillosis mice and of aspergillosis patients. Based on these findings, it is becoming evident that gliotoxin is produced in the infected organs of patients of aspergillosis at a significant level. In addition to these known mycotoxins, A. fumigatus produces many mycotoxins apparently different from known toxins. From the aspect of gene analysis, the deletion of laeA was found to block the expression of metabolic gene clusters such as sterigmatocystin, and the gene is also expected to be related to the production of gliotoxin. The significance of mycotoxins as virulence factors will hopefully be clarified in the near future.
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日本医真菌学会総会プログラム・抄録集 49 92-92 2005年【目的】Stachybotrys chartarum は土壌や住環境等から検出される真菌である。我々はこれまでに本菌胞子の気道内投与によりマウスの肺の血管周囲間質に炎症細胞浸潤が認められることを明らかにした。そこで今回は本菌を長期間反復投与した場合の肺に及ぼす影響を検討した。<BR>【方法】我国の家屋から分離された S. chartarum の胞子を 2 週間に 3 回ずつ経気道的にマウスに投与し、計 6、8、10、12、18 回投与終了後の肺をはじめとする諸臓器について病理組織学的検討を行った。また血管内皮細胞に本菌の洗浄液を添加して培養し、細胞傷害性及びサイトカインの mRNA 発現を調べた。<BR>【結果および考察】肺動脈周囲に分葉核白血球を含む炎症細胞浸潤が見られるとともに、胞子を6回投与すると肺動脈壁の肥厚が見られ、炎症細胞の消退とともに内腔の狭窄が進行して 10 回以上の投与で内腔の狭窄あるいは閉塞が認められた。これらの血管病変が認められたマウスの割合は 12、18 回投与で 40.0%、63.6% であった。また本菌洗浄液は血管内皮細胞に対し、アポトーシスの誘導、IL-6 の mRNA 発現を亢進させる作用を有していた。本モデルは原発性肺高血圧症（PPH）等のような原因不明の肺循環障害の研究に寄与することが期待され、現在検討を進めている。
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Japanese Journal of Medical Mycology 46(2) 109-117 2005年Stachybotrys chartarum is a dematiaceous fungus that is ubiquitous in our living environment. This fungus has long been regarded as non-pathogenic and its inhalation effect on humans has been scarcely studied. Recently, however, epidemiologic studies on acute idiopathic pulmonary hemorrhage in infants suggested that the fungus might be potentially pathogenic to humans. To determine the pathogenicity of this fungus, its interaction with the host defense system was studied using polymorphonuclear leukocytes (PMNs) and macrophages. Histopathological analysis of mice intratracheally injected with this fungus was also performed. The results disclosed that the conidia of S. chartarum were resistant to the antifungal activities of alveolar macrophages in terms of phagocytosis, killing and inhibition of germination. However, the conidia could not survive in the lungs of mice when injected intratracheally. Lavage fluid of mycelia that contained the dark slimy material coating the surface of conidia showed cytotoxic activity against macrophages and PMNs. Intratracheal injection of conidia in mice resulted in intraalveolar infiltration of PMNs. When using multiple injections during a 3-week period, strong eosinophilic infiltration into the proximal alveoli and perivascular tissues was observed. Our results suggest that inhalation of conidia may cause serious damage to the human lung, particularly when repeated.
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Mycopathologia 158(1) 1-7 2004年7月Aspergillus fumigatus often causes serious health problems. The airway of the human body, the most common initial site of damage, is always exposed to an oxygenated condition, and the oxygen concentration may play a critical role in the virulence of A. fumigatus. In this study, oxygen content, fungal growth, the production of cytotoxic substance(s) in the fungal culture, and their relationship were investigated. Two clinical strains of A. fumigatus were cultured under certain oxygen contents (10, 14 and 20%), and cytotoxicity of their culture filtrates on murine macrophages and their fungal growth were evaluated. The components of these filtrates were analyzed by gas chromatography-mass spectrometry. All culture filtrates contained gliotoxin and showed potent cytotoxicity on macrophages at very low concentration. The amount of gliotoxin in the culture filtrate prepared at 10% oxygen was markedly less, but diminutions in fungal growth and cytotoxicity of this culture filtrate were negligible. These results suggest that a well-oxygenated condition is suitable for the production of gliotoxin by A. fumigatus. A significant role of cytotoxic substances(s) other than gliotoxin is also suggested.
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Mycopathologia 157(3) 245-54 2004年4月Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various, potent bioactivities. However, it has not been considered to be a toxic (or virulence) factor because of its slow production. The aim of the present study was to investigate the effects of aeration on the cytotoxicity of A. fumigatus culture filtrate, and to determine the optimal condition for the rapid production of gliotoxin from this fungus. Fungal culture filtrates were made in three different containers under various conditions of aeration and O2 concentration. These filtrates were compared in terms of their cytotoxicity on murine macrophages and analyzed by gas chromatography. The culture filtrate showed high cytotoxicity when it was made under highly aerated conditions, but it was significantly less cytotoxic when prepared under non-aerated conditions. The cytotoxic activity became evident within 15 h of culture at 20% O2, when the fungus had already started producing gliotoxin. The culture filtrates also contained some other as yet unidentified substances that might also to some extent contribute to the cytotoxicity. In light of these results, the authors propose that a highly aerated condition is responsible for the rapid production of gliotoxin, and that gliotoxin might play an important role in the respiratory infection by A. fumigatus, with other toxic substances acting additively or synergistically.
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Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 9(2) 114-21 2003年6月Invasive aspergillosis has become a serious problem in clinical practice, but the actual factor that confers virulence on the fungus has not been thoroughly elucidated. To identify and isolate the immunosuppressive substances produced by the fungus, the bioactivity of culture filtrates was assessed, and analyses of the culture filtrates were carried out. Culture filtrates from different strains of Aspergillus fumigatus were assessed for their effect on human polymorphonuclear leukocytes and murine macrophages. To assess their activities in vivo, their effect on the survival of mice infected by the fungus was also studied. Subsequently, the composition of the culture filtrates was analyzed by gas chromatography-mass spectrometry. The analyses revealed that the culture filtrates contained gliotoxin at concentrations of 3 to 4 microgram/ml, and some other unidentified compounds. The bioactivities of the culture filtrates were similar to those of gliotoxin. The fungal culture filtrate reduced the survival of infected mice, but the filtrate itself did not cause the death of mice. However, all the bioactivities could not be accounted for by gliotoxin itself. These results indicate that gliotoxin in the culture filtrates may be responsible for part of the immunosuppressive activity, but some other components produced by A. fumigatus contribute, in an additive or synergistic manner, to the virulence of the fungus.
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Nihon Ishinkin Gakkai zasshi = Japanese journal of medical mycology 43(1) 37-41 2002年Aspergillus fumigatus causes serious, life-threatening human infection, and is one of the most important pathogenic fungi. Little is known, however, about its mechanism of infection or its virulence factors. To learn about its virulence factors, the effect of the culture filtrate of A. fumigatus on macrophages was studied. When cocultured with A. fumigatus in 96-well microplates, murine peritoneal macrophages showed significant morphological changes indicating serious cellular damage, even when the macrophages were not in direct contact with the fungus. Then culture filtrates of Aspergillus spp., A. fumigatus, A. flavus, A. terreus and A. niger, were prepared by culturing the fungus in 96-well or 24-well microplates for 24 h, and the effect of the culture filtrates was determined by culturing macrophages with or without culture filtrate. When cultured with the culture filtrate of A. fumigatus at a concentration of 1% or higher, macrophages demonstrated significant morphological changes, leading to their death. Treatment with heat greatly lowered the activity of the culture filtrate. In contrast, culture filtrates of A. terreus and A. flavus showed no detectable effect on macrophages, whereas A. niger did display a similar, but much weaker effect. Our study strongly suggests that A. fumigatus releases a toxic product (s) in the medium very rapidly, and this may be critically involved as the virulence factor in human infection, at least in part, by causing serious injury to macrophages.
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European Respiratory Journal 19(1) 195-198 2002年Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene. The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent. To the best of the authors' knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.
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European Respiratory Journal 19(1) 195-198 2002年Ehlers-Danlos syndrome type IV (EDS IV) is caused by mutation within the COL3A1 gene, resulting in the disorder of type III procollagen. The diagnosis is confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts or by identifying the mutation in the COL3A1 gene. The authors report a case of EDS IV caused by a novel point mutation in the COL3A1 gene in a 16-yr-old female. Recurrent haemoptysis and cavitary formation of the lung were evidence of pulmonary involvement. However, extrathoracic manifestations of EDS IV were mostly absent. To the best of the authors' knowledge, all previously reported Ehlers-Danlos syndrome IV patients with respiratory disease had the characteristic findings or histories of Ehlers-Danlos syndrome IV. In the present case, connective tissue friability was suspected due to tissue laceration observed in the biopsied lung specimen, and the diagnosis was made beginning from this pivotal finding.