Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways

Naoko Iwata-Yoshikawa, Masatoshi Kakizaki, Nozomi Shiwa-Sudo, Takashi Okura, Maino Tahara, Shuetsu Fukushi, Ken Maeda, Miyuki Kawase, Hideki Asanuma, Yuriko Tomita, Ikuyo Takayama, Shutoku Matsuyama, Kazuya Shirato, Tadaki Suzuki, Noriyo Nagata () and Makoto Takeda ()
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Naoko Iwata-Yoshikawa: National Institute of Infectious Diseases
Masatoshi Kakizaki: National Institute of Infectious Diseases
Nozomi Shiwa-Sudo: National Institute of Infectious Diseases
Takashi Okura: National Institute of Infectious Diseases
Maino Tahara: National Institute of Infectious Diseases
Shuetsu Fukushi: National Institute of Infectious Diseases
Ken Maeda: National Institute of Infectious Diseases
Miyuki Kawase: National Institute of Infectious Diseases
Hideki Asanuma: National Institute of Infectious Diseases
Yuriko Tomita: National Institute of Infectious Diseases
Ikuyo Takayama: National Institute of Infectious Diseases
Shutoku Matsuyama: National Institute of Infectious Diseases
Kazuya Shirato: National Institute of Infectious Diseases
Tadaki Suzuki: National Institute of Infectious Diseases
Noriyo Nagata: National Institute of Infectious Diseases
Makoto Takeda: National Institute of Infectious Diseases

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract In cultured cells, SARS-CoV-2 infects cells via multiple pathways using different host proteases. Recent studies have shown that the furin and TMPRSS2 (furin/TMPRSS2)-dependent pathway plays a minor role in infection of the Omicron variant. Here, we confirm that Omicron uses the furin/TMPRSS2-dependent pathway inefficiently and enters cells mainly using the cathepsin-dependent endocytosis pathway in TMPRSS2-expressing VeroE6/TMPRSS2 and Calu-3 cells. This is the case despite efficient cleavage of the spike protein of Omicron. However, in the airways of TMPRSS2-knockout mice, Omicron infection is significantly reduced. We furthermore show that propagation of the mouse-adapted SARS-CoV-2 QHmusX strain and human clinical isolates of Beta and Gamma is reduced in TMPRSS2-knockout mice. Therefore, the Omicron variant isn’t an exception in using TMPRSS2 in vivo, and analysis with TMPRSS2-knockout mice is important when evaluating SARS-CoV-2 variants. In conclusion, this study shows that TMPRSS2 is critically important for SARS-CoV-2 infection of murine airways, including the Omicron variant.

Date: 2022
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DOI: 10.1038/s41467-022-33911-8

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