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

被引：54

作者：

Hashimoto, Rina ^{[1
]}

Takahashi, Junya ^{[2
]}

Shirakura, Keisuke ^{[2
]}

Funatsu, Risa ^{[2
]}

Kosugi, Kaori ^{[1
]}

Deguchi, Sayaka ^{[1
]}

Yamamoto, Masaki ^{[3
]}

Tsunoda, Yugo ^{[4
,5
]}

Morita, Maaya ^{[2
]}

Muraoka, Kosuke ^{[2
]}

Tanaka, Masato ^{[2
]}

Kanbara, Tomoaki ^{[2
]}

Tanaka, Shota ^{[2
]}

Tamiya, Shigeyuki ^{[6
]}

Tokunoh, Nagisa ^{[6
,7
]}

Kawai, Atsushi ^{[2
,6
]}

Ikawa, Masahito ^{[2
,6
,8
]}

Ono, Chikako ^{[6
,8
]}

Tachibana, Keisuke ^{[2
]}

Kondoh, Masuo ^{[2
]}

Obana, Masanori ^{[2
,9
,10
]}

Matsuura, Yoshiharu ^{[6
,8
]}

Ohsumi, Akihiro ^{[11
]}

Noda, Takeshi ^{[4
,5
]}

Yamamoto, Takuya ^{[1
,12
,13
]}

Yoshioka, Yasuo ^{[2
,7
,8
,9
,10
]}

Torisawa, Yu-Suke ^{[14
]}

Date, Hiroshi ^{[11
]}

Fujio, Yasushi ^{[2
,8
,9
]}

Nagao, Miki ^{[3
]}

Takayama, Kazuo ^{[1
,15
]}

Okada, Yoshiaki ^{[2
,8
]}

机构：

[1] Kyoto Univ, Ctr iPS Cell Res & Applicat CiRA, Kyoto 6068507, Japan

[2] Osaka Univ, Grad Sch Pharmaceut Sci, Osaka 5650871, Japan

[3] Kyoto Univ, Grad Sch Med, Dept Clin Lab Med, Kyoto 6068303, Japan

[4] Kyoto Univ, Inst Life & Med Sci, Lab Ultrastruct Virol, Kyoto 6068507, Japan

[5] Kyoto Univ, Grad Sch Biostudies, Lab Ultrastruct Virol, Kyoto 6068507, Japan

[6] Osaka Univ, Res Inst Microbial Dis, Osaka 5650871, Japan

[7] Osaka Univ, BIKEN Ctr Innovat Vaccine Res & Dev, Res Fdn Microbial Dis, Osaka 5650871, Japan

[8] Osaka Univ, Ctr Infect Dis Educ & Res CiDER, Osaka 5650871, Japan

[9] Osaka Univ, Inst Open & Transdisciplinary Res Initiat, Osaka 5650871, Japan

[10] Osaka Univ, Global Ctr Med Engn & Informat, Osaka 5650871, Japan

[11] Kyoto Univ Hosp, Dept Thorac Surg, Kyoto 6068507, Japan

[12] RIKEN, Ctr Adv Intelligence Project AIP, Med Risk Avoidance Based iPS Cells Team, Kyoto 6068507, Japan

[13] Kyoto Univ, Inst Adv Study Human Biol WPI ASHBi, Kyoto 6068501, Japan

[14] Kyoto Univ, Dept Micro Engn, Kyoto 6158540, Japan

[15] Japan Agcy Med Res & Dev AMED, AMED CREST, Tokyo 1000004, Japan

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 38期

关键词：

BLOOD-BRAIN-BARRIER; ENDOTHELIAL-CADHERIN; ADHERENS JUNCTIONS; VE-CADHERIN; INFECTION; ADHESION;

D O I：

10.1126/sciadv.abo6783

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-2induced 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.

引用

页数：15

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