MEDICAL MYCOLOGY RESEARCH CENTER
MANIPULATING MICROBES FOR HUMAN HEALTH
-Detailed investigations of host–microbe interactions could yield new therapies against infectious agents and autoimmune diseases.
Research Keywords: Infection and Immunity, Microbiota, Superorganism
The human body is made up of a staggering 30 trillion cells or so. But just as numerous, if not more so, are the several hundred trillions of microbial co-inhabitants that teem in and on us. These microbiotas are essential to our well-being, and a distortion in its balance can trigger a wide range of disorders.
Only recently, however, have scientists come to appreciate just how critical this collection of microbiota is for determining human health and disease. They are also becoming excited about the prospect of how manipulating this microbial ecosystem could form the basis for the next generation of life-saving therapeutics. Led by Mitsutoshi Yoneyama, researchers at the Medical Mycology Research Center have launched a comprehensive research effort to dissect the intricacies of host-microbe interactions in the skin, lung, intestines, and bone marrow.
“Dysregulation of host-microbe interactions can give rise to a wide variety of human disorders, including opportunistic infections, allergies, and autoimmune disease,” explains Yoneyama. “It is hence crucial to understand how hosts and commensal microbes communicate as a superorganism.”
Creating a superorganism is an apt metaphor for what Yoneyama is trying to achieve because, through the melding of minds from across Chiba and around the world, the center can make a far greater impact than any individual scientist working independently.
At Chiba University, the investigators come from the Medical Mycology Research Center, the Graduate School of Medicine, and the Graduate School of Pharmaceutical Sciences, while external collaborators are based in the United States, Germany, and elsewhere in Japan. These scholars, together with others from around the world, convene each November at the Medical Mycology Research Center for the annual Global Network Forum on Infection and Immunity.
EXPLORING HOST–MICROBE INTERACTIONS
The team that Yoneyama has put together is roughly divided into four groups, each studying molecular interactions in different host–microbial systems. One, led by Shinobu Saijo and Yuumi Nakamura Matsuoka, is focused on fungal infections in the skin of mice and humans; another, led by Koichi Hirose, Tomohiro Tamachi, and Arifumi Iwata is investigating the microbes — both good and bad — that reside in the respiratory tract. A third group, which includes Yoshiyuki Goto, Hiroshi Ashida, and Kinnosuke Yahiro, is concentrating on the gut microbiome and how opportunistic intestinal infections gain a foothold; while the fourth, led by Akiko Takaya, is working on more basic mechanisms of immuno- logical memory in response to microbial invaders.
“Results obtained from our projects will help efforts to create innovative new therapeutics against infectious diseases and will eventually lead to improvements in human health,” says Yoneyama, whose own research focuses on the mechanisms of innate antiviral immunity with Koji Onomoto.
To assist all these research projects, investigators from each group have access to the Japanese government’s network of core facilities — a resource known as the Joint Usage/Research Center, which is staffed by specialized researchers and technicians who can run state-of-the art experiments, including with fungi and other microbes. A bioinformatics unit at Chiba led by Hiroki Takahashi helps with computational analyses.（CHIBA RESEARCH 2020）
|Name||Title, Affiliation||Research Themes|
|YONEYAMA Mitsutoshi||Professor, Medical Mycology Research Center||Virology and Immunology|
|Name||Title, Affiliation||Research Themes|
|SAIJO Shinobu||Associate Professor, Medical Mycology Research Center||Mycology and Immunology|
|HIROSE Koichi||Specially Appointed Professor, Graduate School of Medicine||Allergy and Clinical Immunology|
|TAMACHI Tomohiro||Associate Professor, Graduate School of Medicine||Allergy and Clinical Immunology|
|TAKAYA Akiko||Associate Professor, Graduate School of Pharmaceutical Science||Bacteriology|
|GOTO Yoshiyuki||Associate Professor, Medical Mycology Research Center||Mucosal Immunology and Bacteriology|
|ASHIDA Hiroshi||Visiting Associate Professor, Medical Mycology Research Center||Bacteriology|
|YAHIRO Kinnosuke||Associate Professor, Graduate School of Medicine||Bacteriology|
|IWATA Arifumi||Associate Professor, Graduate School of Medicine||Allergy and Clinical Immunology|
|ONOMOTO Koji||Associate Professor, Medical Mycology Research Center||Viral Immunology|
Recent findings have demonstrated that commensal microbes play an essential role in the maintenance of host homeostasis. In this project, we focus on an understanding of the molecular interactions between hosts and microbes, especially commensal fungi and bacteria, using the model assay system of skin, respiratory, and digestive organs of mice and humans. We also aim to reveal the molecular machinery underlying the disruption of the homeostatic balance by invasive pathogens and the pathogenesis of infectious diseases. The findings obtained from our project will help develop innovative interventions in the therapeutics of infectious diseases. In the past three years, we have collaborated on the projects within the group in addition to the individual research projects and published about 70 research papers in various international journals.
Dr. Matsuoka, in collaboration with Dr. Gabriel Nunez (Michigan Univ.) and Dr. Saijo, elucidated the regulatory mechanism of skin inflammation in response to epicutaneous Staphylococcus aureus infection (Cell Host Microbe, 2017). This research received the Excellent Presentation Award at the GP symposium in 2017. Dr. Saijo and Dr. Yoichiro Iwakura’s group (Tokyo Univ. Sci.) published a research paper showing that the secretion of interleukin (IL)-17F is involved in microbiota-mediated colitis development (Nat Immunol, 2018). Dr. Hirose and Dr. Tamachi, in collaboration with Dr. Goto, reported that IL-22, which is mainly secreted by CD4+ T cells, has a protective role in the development of house dust mite (HDM)-induced allergic inflammation. (J Exp Med, 2017) . The senior author of this paper, Dr. Ito, received the Best Presentation Award at the annual meeting of Japanese Society for Immunology in 2017. Furthermore, Dr. Hirose and Dr. Tamachi, in collaboration with Dr. Saijo, demonstrated that Dectin-1 recognizes specific molecules in HDM and induces allergic airway inflammation (J Immunol, 2017). Dr. Goto and Dr. Ashida successfully developed mouse intestinal Candida and Shigella infection models, respectively. Using this model system, Dr. Goto recently demonstrated that commensal microbes prevent the colonization of the pathogenic fungus, Candida albicans, in the gastrointestinal (GI) tract (Microbiol Immunol. 2019). Moreover, he published a review article outlining the regulatory mechanism of glycosylation in the GI tract and interaction with microbiota and pathogenic bacteria (Nat Immunol, 2016), and received the Young Scientists’ Prize of the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science, and Technology, in 2017. Dr. Takaya, in collaboration with Dr. Koji Tokoyoda (Deutsches Rheuma-Forschungszentrum, Germany), discovered that the protein produced by the latently infected Salmonella inhibited secretion of IgG from plasma cells in the bone marrow (Proc Natl Acad Sci USA, 2019).
As part of the establishment of a research center, we installed a germ-free mouse facility in Medical Mycology Research Center (MMRC), and started research from April 2018. Also, to expand international collaborative research, we have been co-hosting the Global Network Forum that is held once a year at MMRC.
To summarize, according to our original plan of the project, all groups have performed their research well and achieved excellent results via collaborative science. Given a comprehensive understanding of the findings obtained from the project, we will proceed with analysis focusing on the maintenance of the host homeostasis as a "superorganism" and try to develop novel strategies for the treatment/prevention of infectious diseases.