次世代シークエンサーを活用したオミクス解析によるAspergillus fumigatus 病原因子探索
アスペルギルス症の主要な原因菌であるAspergillus fumigatus のゲノムが公開されてから15年が経とうとしている．ゲノム解読株（Af 293株）を基準とした病原因子解析が世界中の研究者によって進められ，感染機構に関して多くの知見がもたらされたことは論を俟たない．一方で，単一のゲノム解読株に依拠した病原因子解析が，実際のヒト感染における複雑な臨床的側面を説明しうるかについては議論の余地がある．したがって，臨床的観点から病原菌の振る舞いを詳細に理解することが，今後の感染微生物学における課題だと考えられる．当グループは近年，多数の臨床分離株を対象として遺伝的，生理的，感染病理的知見を...
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| Published in | Medical Mycology Journal Vol. 59; no. 2; pp. J35 - J40 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
Tokyo
日本医真菌学会
01.01.2018
Japan Science and Technology Agency |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2185-6486 2186-165X |
| DOI | 10.3314/mmj.18.005 |
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| Abstract | アスペルギルス症の主要な原因菌であるAspergillus fumigatus のゲノムが公開されてから15年が経とうとしている．ゲノム解読株（Af 293株）を基準とした病原因子解析が世界中の研究者によって進められ，感染機構に関して多くの知見がもたらされたことは論を俟たない．一方で，単一のゲノム解読株に依拠した病原因子解析が，実際のヒト感染における複雑な臨床的側面を説明しうるかについては議論の余地がある．したがって，臨床的観点から病原菌の振る舞いを詳細に理解することが，今後の感染微生物学における課題だと考えられる．当グループは近年，多数の臨床分離株を対象として遺伝的，生理的，感染病理的知見を集積することにより，上記課題の解決を目指した研究を開始している．本稿では，次世代シークエンサーを活用した臨床分離株の大規模遺伝子解析について，特に病原性，感染形態，薬剤耐性に焦点を当てて紹介する．われわれのアプローチは，病原菌の株単位に存在する遺伝的差異と表現型との連関解析に基づいたものであり，今後，基準株の解析のみからは得られない病原性に関する新しい知見がもたらされると期待される． |
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| AbstractList | アスペルギルス症の主要な原因菌であるAspergillus fumigatus のゲノムが公開されてから15年が経とうとしている．ゲノム解読株（Af 293株）を基準とした病原因子解析が世界中の研究者によって進められ，感染機構に関して多くの知見がもたらされたことは論を俟たない．一方で，単一のゲノム解読株に依拠した病原因子解析が，実際のヒト感染における複雑な臨床的側面を説明しうるかについては議論の余地がある．したがって，臨床的観点から病原菌の振る舞いを詳細に理解することが，今後の感染微生物学における課題だと考えられる．当グループは近年，多数の臨床分離株を対象として遺伝的，生理的，感染病理的知見を集積することにより，上記課題の解決を目指した研究を開始している．本稿では，次世代シークエンサーを活用した臨床分離株の大規模遺伝子解析について，特に病原性，感染形態，薬剤耐性に焦点を当てて紹介する．われわれのアプローチは，病原菌の株単位に存在する遺伝的差異と表現型との連関解析に基づいたものであり，今後，基準株の解析のみからは得られない病原性に関する新しい知見がもたらされると期待される． Aspergillus fumigatus is the predominant fungal pathogen responsible for life-threatening systemic infections in humans. Recently developed high-throughput whole genome sequencing (WGS) and RNA-Seq technologies have proven to be powerful tools for systematically investigating pathogenic organisms. In this review, we present new virulence factors obtained through our “omics” researches on A. fumigatus. We first sequenced genomes of A. fumigatus stains isolated from one infected patient at different time points, and made an important finding that although the genome (microsatellites) type of the infected strain remained unchanged, the strain exhibited several genetic changes, including acquiring therapeutic drug resistance, during patient treatment for 1.5 years. Of the various presentations of aspergillosis, pulmonary aspergilloma (PA) is one of the most common forms of A. fumigatus infection, where fungus balls are composed of fungal hyphae, inflammatory cells, fibrin, mucus, and tissue debris. Chronic necrotizing pulmonary aspergillosis (CNPA), also known as semi-invasive or invasive aspergillosis, is locally invasive and predominantly seen in patients with mild immunodeficiency or with a chronic lung disease. We compared genomes of strains individually isolated from eight PA and eight CNPA patients in Japan, and found that the PA and CNPA strains show indiscernible genetic and ancestral backgrounds as far as genomic SNPs of the strains are concerned. The main route of infections caused by A. fumigatus is via inhalation of conidia. Inhaled conidia rapidly adhere to pulmonary epithelial cells. Nevertheless, little is known of the molecular mechanism of adherence in A. fumigatus resting conidia. We assumed corresponding adhesion molecules were highly expressed in high-adhesion conidia during conidia maturation, and exhaustively searched adhesion molecules by comparing gene expression levels in high- and low-adherence strains using the RNA-Seq technique. We found several factors involved in conidial adhesion and suggest that composite actions of these molecules have roles in conidial adhesion to human pulmonary epithelial cells. |
| Author | 萩原, 大祐 渡辺, 哲 豊留, 孝仁 五ノ井, 透 髙橋, (中口) 梓 高橋, 弘喜 亀井, 克彦 酒井, 香奈江 |
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| References | 3) Kousha M, Tadi R, Soubani AO: Pulmonary aspergillosis: a clinical review. Eur Respir Rev 20: 156-174, 2011. 1) Denning DW, Anderson MJ, Turner G, Latgé JP, Bennett JW: Sequencing the Aspergillus fumigatus genome. Lancet Infect Dis 2: 251-253, 2002. 4) Denning DW: Chronic forms of pulmonary aspergillosis. Clin Microbiol Infect 7 Suppl 2: 25-31, 2001. 9) Sheppard DC: Molecular mechanism of Aspergillus fumigatus adherence to host constituents. Curr Opin Microbiol 14: 375- 379, 2011. 8) Takahashi-Nakaguchi A, Muraosa Y, Hagiwara D, Sakai K, Toyotome T, Watanabe A, Kawamoto S, Kamei K, Gonoi T, Takahashi H: Genome sequence comparison of Aspergillus fumigatus strains isolated from patients with pulmonary aspergilloma and chronic necrotizing pulmonary aspergillosis. Med Mycol 53: 353-360, 2015. 7) Xu H, Li LJ, Wan Z, Li RY, Liu W: Dexamethasone increases susceptibility of Aspergillus fumigatus to hydrogen peroxide via down-regulation of Afyap1 gene expression in vitro. Chin Med J (Engl) 124: 3773-3777, 2011. 10) Takahashi-Nakaguchi A, Sakai K, Takahashi H, Hagiwara D, Toyotome T, Chibana H, Watanabe A, Yaguchi T, Yamaguchi M, Kamei K, Gonoi T: Aspergillus fumigatus adhesion factors in dormant conidia revealed through comparative phenotypic and transcriptomic analyses. Cell Microbiol 30: doi: 10.1111/cmi.12802. 5) Hagiwara D, Takahashi H, Watanabe A, Takahashi-Nakaguchi A, Kawamoto S, Kamei K, Gonoi T: Whole-genome comparison of Aspergillus fumigatus strains serially isolated from patients with aspergillosis. J Clin Microbiol 52: 4202- 4209, 2014. 6) Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, Verweij PE, Melchers WJ: Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PLoS One 7: e50034, 2012. 2) Greene R: The pulmonary aspergilloses: three distinct entities or a spectrum of disease. Radiology 140: 527-530, 1981. |
| References_xml | – reference: 4) Denning DW: Chronic forms of pulmonary aspergillosis. Clin Microbiol Infect 7 Suppl 2: 25-31, 2001. – reference: 1) Denning DW, Anderson MJ, Turner G, Latgé JP, Bennett JW: Sequencing the Aspergillus fumigatus genome. Lancet Infect Dis 2: 251-253, 2002. – reference: 6) Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, Verweij PE, Melchers WJ: Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PLoS One 7: e50034, 2012. – reference: 8) Takahashi-Nakaguchi A, Muraosa Y, Hagiwara D, Sakai K, Toyotome T, Watanabe A, Kawamoto S, Kamei K, Gonoi T, Takahashi H: Genome sequence comparison of Aspergillus fumigatus strains isolated from patients with pulmonary aspergilloma and chronic necrotizing pulmonary aspergillosis. Med Mycol 53: 353-360, 2015. – reference: 5) Hagiwara D, Takahashi H, Watanabe A, Takahashi-Nakaguchi A, Kawamoto S, Kamei K, Gonoi T: Whole-genome comparison of Aspergillus fumigatus strains serially isolated from patients with aspergillosis. J Clin Microbiol 52: 4202- 4209, 2014. – reference: 9) Sheppard DC: Molecular mechanism of Aspergillus fumigatus adherence to host constituents. Curr Opin Microbiol 14: 375- 379, 2011. – reference: 2) Greene R: The pulmonary aspergilloses: three distinct entities or a spectrum of disease. Radiology 140: 527-530, 1981. – reference: 3) Kousha M, Tadi R, Soubani AO: Pulmonary aspergillosis: a clinical review. Eur Respir Rev 20: 156-174, 2011. – reference: 10) Takahashi-Nakaguchi A, Sakai K, Takahashi H, Hagiwara D, Toyotome T, Chibana H, Watanabe A, Yaguchi T, Yamaguchi M, Kamei K, Gonoi T: Aspergillus fumigatus adhesion factors in dormant conidia revealed through comparative phenotypic and transcriptomic analyses. Cell Microbiol 30: doi: 10.1111/cmi.12802. – reference: 7) Xu H, Li LJ, Wan Z, Li RY, Liu W: Dexamethasone increases susceptibility of Aspergillus fumigatus to hydrogen peroxide via down-regulation of Afyap1 gene expression in vitro. Chin Med J (Engl) 124: 3773-3777, 2011. |
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| Title | 次世代シークエンサーを活用したオミクス解析によるAspergillus fumigatus 病原因子探索 |
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