Sci Adv . SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

[tetano]

Sci Adv


. 2022 Sep 23;8(38):eabo6783.
doi: 10.1126/sciadv.abo6783. Epub 2022 Sep 21.
SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression


Rina Hashimoto ¹ , Junya Takahashi ² , Keisuke Shirakura ² , Risa Funatsu ² , Kaori Kosugi ¹ , Sayaka Deguchi ¹ , Masaki Yamamoto ³ , Yugo Tsunoda ^{4 5} , Maaya Morita ² , Kosuke Muraoka ² , Masato Tanaka ² , Tomoaki Kanbara ² , Shota Tanaka ² , Shigeyuki Tamiya ⁶ , Nagisa Tokunoh ^{6 7} , Atsushi Kawai ^{2 6} , Masahito Ikawa ^{2 6 8} , Chikako Ono ^{6 8} , Keisuke Tachibana ² , Masuo Kondoh ² , Masanori Obana ^{2 9 10} , Yoshiharu Matsuura ^{6 8} , Akihiro Ohsumi ¹¹ , Takeshi Noda ^{4 5} , Takuya Yamamoto ^{1 12 13} , Yasuo Yoshioka ^{2 6 7 8 9 10} , Yu-Suke Torisawa ¹⁴ , Hiroshi Date ¹¹ , Yasushi Fujio ^{2 8 9} , Miki Nagao ³ , Kazuo Takayama ^{1 15} , Yoshiaki Okada ^{2 8}



Affiliations

• PMID: 36129989
• DOI: 10.1126/sciadv.abo6783

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