Researchers from Japan discover a new enzyme with promising antibacterial activity
Acute graft-versus-host disease (aGVHD) is a medical condition that occurs when donor immune cells attack the recipient's tissues after an allogeneic hematopoietic stem cell transplantation (allo-HCT). The pathogenesis of aGVHD is influenced by gut dysbiosis and Enterococcus domination. Researchers from Japan recently identified a bacteriophage-derived enzyme called endolysin capable of targeting biofilms formed by Enterococcus faecalis. Their findings offer hope for tailored interventions in allo-HCT.
Allogenic haematopoietic cell transplantation (allo-HCT) involves transferring healthy donor stem cells to recipients with conditions like blood cancer, bone marrow failure, or certain genetic blood disorders. Acute graft-versus-host disease (aGVHD) is a common complication, where the donor's immune cells attack the recipient's tissues. Recent studies highlight the significant role of the microbiome in aGVHD, with dysbiosis contributing to its pathogenesis. Dysbiosis can lead to the emergence of pathogenic commensal bacteria including Enterococcus species, particularly E. faecalis and E. faecium, which are associated with multidrug-resistant infections in allo-HCT patients. However, there is a lack of effective therapies specifically tailored to treat dysbiosis in the context of aGVHD.
To address this gap, a multidisciplinary team led by Associate Professor Kosuke Fujimoto from Osaka Metropolitan University and The University of Tokyo, alongside Professor Seiya Imoto from The University of Tokyo, and Satoshi Uematsu from Osaka Metropolitan University and The University of Tokyo, conducted an in-depth analysis of the intestinal bacteriome of allo-HCT patients. The study aimed to investigate the prevalence and implications of Enterococcus domination in this specific patient population. Their findings, published on July 10, 2024, in the journal Nature, shed light on crucial aspects of gut microbiota dynamics in the context of allo-HCT.
Explaining the motivation behind the present research, Fujimoto says, “During dysbiosis, some symbiotic commensal bacteria acquire pathogenic characteristics, proliferate, and become directly involved in the onset and progression of the disease. Recognizing the specificity of phage therapy and its ability to spare beneficial bacteria from adverse effects, we focused our research on phage-derived lytic enzymes.”
The team initiated their investigation by examining the intestinal microbiome of allo-HCT patients, where they noted a predominance of Enterococcus species, particularly E. faecalis. This was notably associated with acute leukemia. Despite being sensitive to several antibiotics, E. faecalis strains possessed cytolysin-associated genes, indicating high virulence. Further exploration through metagenomic analysis revealed the presence of genetic signatures associated with biofilm formation. They then proceeded with whole-genome sequencing of E. faecalis. This unveiled the presence of an intriguing bacteriophage-derived enzyme known as endolysin, exhibiting potent antibacterial activity specifically targeting E. faecalis.
Fujimoto and his team conducted rigorous in-vitro and in-vivo assays to confirm the efficacy of the endolysin. They found that it exhibited narrow-spectrum activity against E. faecalis and effectively lysed biofilms. Notably, the endolysin's lytic activity did not affect other intestinal bacteria species. In mouse models, the efficacy of the endolysin was assessed in two experiments. Firstly, mice with induced aGVHD were treated with the endolysin, resulting in a significant reduction of E. faecalis colonization in faeces and suppression of aGVHD development. In the second experiment, mice with a gut microbiota resembling that of humans, dominated by Enterococcus bacteria, were treated with the endolysin, leading to decreased Enterococcus levels and improved survival rates.
“Bacteriophage research is gaining momentum, with advancements in phage therapy paving the way for new treatments. Our discovery of the endolysin enzyme holds promise for future applications in preventing or treating acute GVHD,” says Fujimoto, expressing his optimism regarding the potential impact and real-life applications of the research work.
Thanks to the research team for the identification of endolysin from bacteriophage, a new class of therapeutic compounds targeting highly resistant, biofilm-forming bacteria is now possible!
Identification of bacteriophage-derived enzyme and its antibacterial activity can contribute to novel therapies that target biofilm-forming bacteria and help in the treatment against acute graft-versus-
host disease.
Reference
Journal：
Nature
Title of original paper：
An enterococcal phage-derived enzyme suppresses graft-versus-host disease
Nature
Title of original paper：
An enterococcal phage-derived enzyme suppresses graft-versus-host disease
DOI：
10.1038/s41586-024-07667-8
Authors：
Kosuke Fujimoto1,2,*, Tetsuya Hayashi1,3,*, Mako Yamamoto4, Noriaki Sato4, Masaki Shimohigoshi1, Daichi Miyaoka1, Chieko Yokota1, Miki Watanabe1, Yuki Hisaki1, Yukari Kamei1, Yuki Yokoyama1, Takato Yabuno1, Asao Hirose3, Mika Nakamae3,5, Hirohisa Nakamae3, Miho Uematsu1, Shintaro Sato1,6, Kiyoshi Yamaguchi7, Yoichi Furukawa7, Yukihiro Akeda8, Masayuki Hino3,5, Seiya Imoto4,9, and Satoshi Uematsu1,2,9,10,11
Affiliations：
1. Department of Immunology and Genomics, Graduate School of Medicine, Osaka Metropolitan University
2. Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo
3. Hematology, Graduate School of Medicine, Osaka Metropolitan University
4. Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo
5. Department of Laboratory Medicine and Medical Informatics, Graduate School of Medicine, Osaka Metropolitan University
6. Department of Microbiology and Immunology, School of Pharmaceutical Sciences, Wakayama Medical University
7. Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo
8. Department of Bacteriology I, National Institute of Infectious Diseases
9. Collaborative Research Institute for Innovative Microbiology, The University of Tokyo
10. Reseach Institute for Drug Discovery Science, Osaka Metropolitan University
11. International Research Center for In
fectious Diseases, Osaka Metropolitan University
2. Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo
3. Hematology, Graduate School of Medicine, Osaka Metropolitan University
4. Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo
5. Department of Laboratory Medicine and Medical Informatics, Graduate School of Medicine, Osaka Metropolitan University
6. Department of Microbiology and Immunology, School of Pharmaceutical Sciences, Wakayama Medical University
7. Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo
8. Department of Bacteriology I, National Institute of Infectious Diseases
9. Collaborative Research Institute for Innovative Microbiology, The University of Tokyo
10. Reseach Institute for Drug Discovery Science, Osaka Metropolitan University
11. International Research Center for In
fectious Diseases, Osaka Metropolitan University
About Associate Professor Kosuke Fujimoto from Osaka Metropolitan University and The University of Tokyo, Japan
Kosuke Fujimoto serves as an Associate Professor at Department of Immunology and Genomics, Graduate School of Medicine, Osaka Metropolitan University and a Project Associate Professor at the Division of Metagenome Medicine, The Institute of Medical Science, The University of Tokyo. His research interests include metagenomics, bacteriology, virology, immunology, and life sciences. He has published 36 papers that have been cited more than 1400 times. He has won several awards and honours for his research excellence.UTokyo PEOPLE
Dr. FUJIMOTO Kosuke
About Professor Seiya Imoto from The University of Tokyo, Japan
Seiya Imoto is a Professor at the Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo. He specializes in the application of information technology for analysis of genomic sequencing data and multi-omics data. He has published more than 400 research papers that have been cited over 15200 times. He is currently involved in numerous research projects that utilize multi-omics and genome sequencing analysis.UTokyo PEOPLE
Dr. IMOTO Seiya
About Professor Satoshi Uematsu from Osaka Metropolitan University and The University of Tokyo, Japan
Satoshi Uematsu is a Professor at Department of Immunology and Genomics, Graduate School of Medicine, Osaka Metropolitan University and a Project Professor at the Division of Metagenome Medicine, The Institute of Medical Science, The University of Tokyo. His primary areas of research focus are microbiology, immunology, dysbiosis, and metagenomics. Over the years, he has published more than 200 research papers in high-impact factor journals. He has been conferred with prestigious awards for his research output. He is currently the principal investigator for numerous ongoing research projects.UTokyo PEOPLE
Dr. Uematsu Satoshi
Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp