An article about our laboratory was published in the June 2024 issue of the journal 'Uirus (in Japanese)'.

As it is not published on the web or elsewhere, the full text is available below.

The University of Tokyo Graduate School of Medicine and Faculty of Medicine

Department of Microbiology

Makoto Takeda

Address: 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033

Phone: +81-3-5841-3408

Email: mtakeda@m.u-tokyo.ac.jp

Website: https://microbiology.labby.jp

About the Laboratory

When I began researching viruses in 1995, the professor leading this department was Dr. Hiroshi Yoshikura, who later became the Director of General at the National Institute of Infectious Diseases. At that time, the main research focus was on elucidating the replication mechanisms of retroviruses using mouse retroviruses, along with cutting-edge research on hepatitis C virus and other topics.

In 2000, Dr. Akio Nomoto, who later received the Japan Academy Prize, succeeded Dr. Yoshikura as the professor. Dr. Nomoto's primary research topics were on the replication and pathogenesis of poliovirus, with significant achievements in translation control via the internal ribosome entry site (IRES) and studies on the poliovirus receptor.

In 2010, Dr. Masanori Hatakeyama succeeded Dr. Nomoto as the professor. Dr. Hatakeyama made significant discoveries on how the CagA protein of Helicobacter pylori induces gastric cancer, earning the Takeda Prize for Medical Science for his outstanding achievements. On September 1, 2022, I was appointed as the professor in this department, succeeding Dr. Hatakeyama.

Associate Professor Dr. Hiroshi Katoh, the head of the Mumps laboratory in the Department of Virology 3 at the National Institute of Infectious Diseases, where I previously served as the Director, joined on the same day I assumed my position, and we began managing the laboratory together. On December 1, 2022, Dr. Yukiko Akahori, previously a member of the Influenza Vaccine laboratory in the same institute, joined us as an assistant professor. On April 1, 2023, Dr. Yuki Kitai, who had just completed a PhD at Tohoku University and was affiliated with the Virus Research Center at the Sendai Medical Center, joined as an assistant professor. With this, our laboratory staff was fully established. The laboratory is located on the south side of the 10th floor of the Medical Experimental Research Building on the Hongo Campus of the University of Tokyo.

It has been about 1 year and 9 months since I took my position. Our current laboratory consists of one professor, one associate professor, two assistant professors, two technical assistants, one special research student (4th-year doctoral course), two first-year postgraduate students, and five medical students (two 5th-year, two 4th-year, and one 3rd-year) who are participating through programs, the Medical Scientist Training Program of the University of Tokyo, Faculty of Medicine. The laboratory is full of energy, driven by the enthusiasm and talent of these young individuals. We are all working daily to contribute significantly to science and society through pathogen research and to train many individuals who will lead the next generation.

Research Overview

1.    Research on the Host Range and Antigenic Determinants of Morbilliviruses

Morbilliviruses, a genus of the Paramyxoviridae family, include various animal viruses such as measles virus. We study the molecular mechanisms determining the host range of morbilliviruses by analyzing receptors like SLAM and Nectin-4 and the species-specific differences in innate immune responses. Through this, we aim to deepen our understanding of the measles virus and elucidate the molecular basis of morbilliviruses' evolution and cross-species transmission. Additionally, while measles virus is known for its stable antigenicity, the antigenic cross-reactivity among closely related morbilliviruses is not very high. We aim to broaden our understanding of viruses by unraveling these molecular bases.

2.    Research on the RNA Synthesis Mechanisms of Paramyxoviruses

Upon infecting cells, paramyxoviruses form non-membranous structures called inclusion bodies in the cytoplasm, where RNA synthesis occurs. Our laboratory primarily uses the mumps virus, a member of the Paramyxoviridae family, to analyze the mechanisms of inclusion body formation and the functions of host factors recruited into these structures. We have previously reported that the chaperone protein Heat Shock Protein 90 plays a crucial role in the maturation of mumps virus polymerase protein and that the R2TP complex contributes to efficient viral replication by controlling viral RNA synthesis. We are currently using confocal laser, super-resolution, and electron microscopy to elucidate the detailed structure of inclusion bodies. Furthermore, we use spatial transcriptomics and proximity-dependent labeling methods to identify host RNAs and proteins present in inclusion bodies and analyze their functions.

3.    Research on Respiratory Viruses and Host Proteases

Host cell proteases activate the fusion proteins of many viruses. Thus, the proteases each virus can utilize and the tissues (cells) expressing these proteases are closely related to the virus's pathogenesis. We have shown that the type II transmembrane serine protease TMPRSS2 plays a critical role in the infection of respiratory viruses, including influenza virus, parainfluenza virus, pneumovirus, and coronavirus. This knowledge was highly beneficial in the national and international responses to the COVID-19 pandemic. We are continuing to elucidate the replication mechanisms of various respiratory viruses, including the involvement of other proteases, using animal and organoid models.

4.    Research on Henipavirus Glycoproteins and Vaccine Development

Due to their high risk, the Nipah virus and Hendra virus, classified under the genus Henipavirus of the Paramyxoviridae family, are classified as BSL-4 pathogens. Recently, a diverse range of henipaviruses have been discovered. Our laboratory focuses on the Paramyxoviridae family of viruses, and we have a strong interest in henipaviruses. We are currently analyzing the viral glycoproteins responsible for receptor binding and membrane fusion in multiple henipaviruses. Additionally, we are researching to develop henipavirus vaccines using other safer paramyxoviruses as vectors.

5.    Research on the Development of Virus Vectors Using Optogenetics

The Paramyxoviridae family includes various pathogens that cause diseases in humans and animals. Efforts to utilize these viruses in gene therapy, cancer therapy, regenerative medicine, and other applications are underway. We have developed technologies to control the replication of Paramyxoviridae viruses using optogenetics. We are currently starting research to use these optogenetically controlled viruses as oncolytic vectors for cancer therapy. We plan to continue developing virus vectors incorporating various advanced technologies.

Vision

In 2020, we experienced a pandemic described as a once-in-a-century event. In my previous position at the Department of Virology 3 at the National Institute of Infectious Diseases, which was responsible for laboratories and vaccines for respiratory viruses, including coronaviruses, I had the opportunity to gain valuable experiences, such as the diagnosis of the first domestic case, the nationwide expansion of testing to local governments, the introduction of vaccines, testing for their introduction, and the national testing after approval. While there were some achievements, such as being able to respond swiftly under challenging circumstances, utilizing the accumulation of research experience, and benefiting from the networks we had built, there were many more things that we were unable to achieve or could not accomplish.

With my new position at the Department of Microbiology at the University of Tokyo, I have shifted from the administrative to the educational field. I plan to solidify the foundation of infectious disease research from a long-term perspective and develop research with free-thinking approaches. Through this, I aim to cultivate a research laboratory that produces many next-generation leaders who will support the foundation of infectious disease research and measures or lead them to the forefront. I would greatly appreciate your continued support and guidance.