Viral uptake and pathophysiology of the lung endothelial cells in age-associated severe SARS-CoV-2 infection models

Takuya Tsumita, Ryo Takeda, Nako Maishi, Yasuhiro Hida, Michihito Sasaki, Yasuko Orba, Akihiko Sato, Shinsuke Toba, Wataru Ito, Takahito Teshirogi, Yuya Sakurai, Tomohiro Iba, Hisamichi Naito, Hitoshi Ando, Haruhisa Watanabe, Amane Mizuno, Toshiki Nakanishi, Aya Matsuda, Ren Zixiao, Ji Won LeeTadahiro Iimura, Hirofumi Sawa, Kyoko Hida

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Thrombosis is the major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the pathology of vascular endothelial cells (ECs) has received much attention. Although there is evidence of the infection of ECs in human autopsy tissues, their detailed pathophysiology remains unclear due to the lack of animal model to study it. We used a mouse-adapted SARS-CoV-2 virus strain in young and mid-aged mice. Only mid-aged mice developed fatal pneumonia with thrombosis. Pulmonary ECs were isolated from these infected mice and RNA-Seq was performed. The pulmonary EC transcriptome revealed that significantly higher levels of viral genes were detected in ECs from mid-aged mice with upregulation of viral response genes such as DDX58 and IRF7. In addition, the thrombogenesis-related genes encoding PLAT, PF4, F3 PAI-1, and P-selectin were upregulated. In addition, the inflammation-related molecules such as CXCL2 and CXCL10 were upregulated in the mid-aged ECs upon viral infection. Our mouse model demonstrated that SARS-CoV-2 virus entry into aged vascular ECs upregulated thrombogenesis and inflammation-related genes and led to fatal pneumonia with thrombosis. Current results of EC transcriptome showed that EC uptake virus and become thrombogenic by activating neutrophils and platelets in the aged mice, suggesting age-associated EC response as a novel finding in human severe COVID-19.

Original languageEnglish
Article numbere14050
JournalAging Cell
Volume23
Issue number2
DOIs
Publication statusPublished - 02-2024

All Science Journal Classification (ASJC) codes

  • Ageing
  • Cell Biology

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