SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression
Rina Hashimoto, Junya Takahashi, Keisuke Shirakura, Risa Funatsu, Kaori Kosugi, Sayaka Deguchi, Masaki Yamamoto, Yugo Tsunoda, Maaya Morita, Kosuke Muraoka, Masato Tanaka, Tomoaki Kanbara, Shota Tanaka, Shigeyuki Tamiya, Nagisa Tokunoh, Atsushi Kawai, Masahito Ikawa, Chikako Ono, Keisuke Tachibana, Masuo Kondoh, Masanori Obana, Yoshiharu Matsuura, Akihiro Ohsumi, Takeshi Noda, Takuya Yamamoto, Yasuo Yoshioka, Yu‐suke Torisawa, Hiroshi Date, Yasushi Fujio, Miki Nagao, Kazuo Takayama, Yoshiaki Okada
Abstract
In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells and then transfers to other organs the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin-mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2-induced respiratory endothelial barrier disruption. We concluded that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2-induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19.