Many viruses have spikes (spike proteins) on the surface of their particles. We have shown that the spike proteins of various respiratory viruses, such as influenza virus and novel coronavirus (SARS-CoV-2), are activated (dramatically increasing infection efficiency) by a protease called TMPRSS2 in the host cell where the virus infects. These results have contributed to the elucidation of the pathogenic mechanism of SARS-CoV-2, countermeasures, vaccine development, and therapeutic drug development. We plan to continue further research on the pathogenesis of respiratory viruses in order to deepen our understanding of respiratory viruses and to prepare for the emergence of new pandemic viruses in the future.

Main Related Publications

1. Kakizaki M, Hashimoto R, Nagata N, Yamamoto T, Okura T, Katoh H, Kitai Y, Akahori Y, Shirato S, Ryo A, Takayama K, Takeda M. The respective roles of TMPRSS2 and cathepsins for SARS-CoV-2 infection in human respiratory organoids. J Virol. 2024 in press.
2. Takeda M. Cleavage activation of respiratory viruses – Half a century of history from Sendai virus to SARS-CoV-2. Jpn J Infect Dis. 77:1-6, 2024
3. Iwata-Yoshikawa N, Kakizaki M, Shiwa-Sudo N, Okura T, Tahara M, Fukushi S, Maeda K, Kawase M, Asanuma H, Tomita Y, Takayama I, Matsuyama S, Shirato K, Suzuki T, Nagata N, Takeda M. Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways. Nat Commun 13: 6100, 2022. Link
4. Takeda M: Proteolytic activation of SARS-CoV-2 spike protein. Microbiol Immunol 66:15-23, 2022.Link
5. Tomita Y, Matsuyama S, Fukuhara H, Maenaka K, Kataoka H, Hashiguchi T, Takeda M: The physiological TMPRSS2 inhibitor HAI–2 alleviates SARS-CoV-2 infection. J Virol 95:e00434–21, 2021.Link
6. Matsuyama S, Nao N, Shirato K, Kawase M, Saito S, Takayama I, Nagata N, Sekizuka T, Katoh H, Kato F, Sakata M, Tahara M, Kutsuna S, Ohmagari N, Kuroda M, Suzuki T, Kageyama T, Takeda M: Enhanced isolation of SARS-CoV-2 by TMPRSS2–expressing cells. Proc Natl Acad Sci U S A 117:7001–7003, 2020.
7. Iwata–Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N: TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol 93:e01815–18, 2019.
8. Sakai K, Sekizuka T, Ami Y, Nakajima N, Kitazawa M, Sato Y, Nakajima K, Anraku M, Kubota T, Komase K, Takehara K, Hasegawa H, Odagiri T, Tashiro M, Kuroda M, Takeda M: A mutant H3N2 influenza virus uses an alternative activation mechanism in TMPRSS2 knockout mice by loss of an oligosaccharide in the hemagglutinin stalk region. J Virol 89:5154–5158, 2015.
9. Sakai K, Ami Y, Tahara M, Kubota T, Anraku M, Abe M, Nakajima N, Sekizuka T, Shirato K, Suzaki Y, Ainai A, Nakatsu Y, Kanou K, Nakamura K, Suzuki T, Komase K, Nobusawa E, Maenaka K, Kuroda M, Hasegawa H, Kawaoka Y, Tashiro M, Takeda M: The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J Virol 88:5608–5616, 2014.
10. Abe M, Tahara M. Sakai K, Yamaguchi H, Kanou K, Shirato K, Kawase M, Noda M, Kimura H, Matsuyama S, Fukuhara H, Mizita K, Maenaka K, Ami Y, Esumi M, Kato A, Takeda M: TMPRSS2 is an activating protease for respiratory parainfluenza viruses. J Virol 87:11930–11935, 2013.
11. Matsuyama S, Nagata N, Shirato, K, Kawase M, Takeda M, Taguchi F: Efficient activation of SARS coronavirus spike protein by the transmembrane protease, TMPRSS2. J Virol 84:12658–12664, 2010.
12. Shirogane Y, Takeda M, Iwasaki M, Ishiguro N, Takeuchi H, Nakatsu Y, Tahara M, Kikuta H, Yanagi Y: Efficient multiplication of human metapneumovirus in Vero cells expressing the transmembrane serine protease TMPRSS2. J Virol 82:8942–8946, 2008.