Clinical Characteristics, Phylogenetic Analysis and Virulence Evolution in the VGI Cryptococcus Gattii Subgroup
Cryptococcus gattii causes cryptococcosis and life-threatening cryptococcal meningitis. In China, VGI is the most prevalent C. gattii genotype, but little is known about the clinical characteristics, phylogenetic relationships and global virulence evolution of VGI strains. First, we showed that the VGI is the predominant genotype of C. gattii in China, and it mostly attacks in immunocompetent populations and its infection has a high mortality rate. Then we subtype and evaluated the global geographic distribution of VGI on (Multilocus sequence typing, MLST) by adding data from published studies, and it was found that the VGI strain is prevalent worldwide, and the most common subtypes are VGIa/VGIb. Most importantly, we performed a phylogenetic analysis on these two subtypes (VGIa/VGIb) using WGS and screened virulence phenotypes with an in vivo mouse model. Obvious phylogenetic differences and virulence differences(p<0.0001) were found within the two `subtypes of VGIa (VGIa.1/VGIa.2). Then the RNA-Seq and DNA-Seq analyses were conducted and two virulence genes, PLC1 and GCN5, were identified. Then the two genes were selected for functional validation, except for the reduction in melanin production and stress response, as previous reports have shown. plc1△ was first found to have a large drug resistance difference compared with that of WT strains. gcn5△ causes capsule deduction, as previous reports have shown. In the Galleria mellonella larvae infection experiment, both mutant strains showed a significant reduction in virulence. Collectively, we found two important virulence genes, PLC1 and GCN5, of VGIa through phylogenetic analysis and an in vivo mouse model, which may be used as potential drug targets for the treatment of C. gattii infection in the future.Funding: This research was funded by National Key Research and Development Program of China (2021YFC2302100); Capital health development scientific research unit matching fund(2020- 2Z-2086); Beijing Hospitals Authority Clinical Medicine Development of special funding support (XMLX202115).Declaration of Interest: We declare no competing interests.Ethical Approval: This study was approved by the Ethics Committee of Beijing Shijitan Hospital and the Animal Experimental Ethics Committee of Beijing Shijitan Hospital. (Protocol code sjtky11-1x-2022 (050)).
| Medienart: |
E-Book |
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| Erscheinungsjahr: |
[2023] |
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| Erschienen: |
S.l.: SSRN ; 2023 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Yemei [VerfasserIn] |
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| Themen: |
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| Umfang: |
1 Online-Ressource (27 p) |
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| doi: |
10.2139/ssrn.4491646 |
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| PPN (Katalog-ID): |
1860104584 |
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| 520 | |a Cryptococcus gattii causes cryptococcosis and life-threatening cryptococcal meningitis. In China, VGI is the most prevalent C. gattii genotype, but little is known about the clinical characteristics, phylogenetic relationships and global virulence evolution of VGI strains. First, we showed that the VGI is the predominant genotype of C. gattii in China, and it mostly attacks in immunocompetent populations and its infection has a high mortality rate. Then we subtype and evaluated the global geographic distribution of VGI on (Multilocus sequence typing, MLST) by adding data from published studies, and it was found that the VGI strain is prevalent worldwide, and the most common subtypes are VGIa/VGIb. Most importantly, we performed a phylogenetic analysis on these two subtypes (VGIa/VGIb) using WGS and screened virulence phenotypes with an in vivo mouse model. Obvious phylogenetic differences and virulence differences(p<0.0001) were found within the two `subtypes of VGIa (VGIa.1/VGIa.2). Then the RNA-Seq and DNA-Seq analyses were conducted and two virulence genes, PLC1 and GCN5, were identified. Then the two genes were selected for functional validation, except for the reduction in melanin production and stress response, as previous reports have shown. plc1△ was first found to have a large drug resistance difference compared with that of WT strains. gcn5△ causes capsule deduction, as previous reports have shown. In the Galleria mellonella larvae infection experiment, both mutant strains showed a significant reduction in virulence. Collectively, we found two important virulence genes, PLC1 and GCN5, of VGIa through phylogenetic analysis and an in vivo mouse model, which may be used as potential drug targets for the treatment of C. gattii infection in the future.Funding: This research was funded by National Key Research and Development Program of China (2021YFC2302100); Capital health development scientific research unit matching fund(2020- 2Z-2086); Beijing Hospitals Authority Clinical Medicine Development of special funding support (XMLX202115).Declaration of Interest: We declare no competing interests.Ethical Approval: This study was approved by the Ethics Committee of Beijing Shijitan Hospital and the Animal Experimental Ethics Committee of Beijing Shijitan Hospital. (Protocol code sjtky11-1x-2022 (050)) | ||
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| 700 | 1 | |a Deng, Hengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yangyu |e verfasserin |4 aut | |
| 700 | 1 | |a Ke, Weixin |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xueqing |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Mei |e verfasserin |4 aut | |
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| 700 | 1 | |a Song, Jialin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xue |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qiqi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xueqing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuo, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Liye |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Xinying |e verfasserin |4 aut | |
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