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

Author

Listed:
  • 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
    The University of Tokyo)

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.

Suggested Citation

  • 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 , 2022. "Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33911-8
    DOI: 10.1038/s41467-022-33911-8
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