tetano
Editor, Senior Moderator
Microbiol Spectr
. 2026 Aug 11:e0131126.
doi: 10.1128/spectrum.01311-26. Online ahead of print.
Revisiting endothelial tropism of SARS-CoV-2 using a cell-specific hACE2 mouse model
Sahine Lameire[SUP] #[/SUP][SUP] 1 2 [/SUP], Nincy Debeuf[SUP] #[/SUP][SUP] 1 2 [/SUP], Julie Deckers[SUP] 1 2 [/SUP], Caroline De Wolf[SUP] 1 2 [/SUP], Manon Vanheerswynghels[SUP] 1 2 [/SUP], Wendy Toussaint[SUP] 1 2 [/SUP], Lize De Vlieger[SUP] 3 4 [/SUP], Lien Van Hoecke[SUP] 3 4 [/SUP], Arnout Bruggeman[SUP] 3 4 5 [/SUP], Sieglinde De Cae[SUP] 6 7 [/SUP], Bert Schepens[SUP] 6 7 [/SUP], Stijn Vanhee[SUP] 1 2 8 [/SUP], Bart N Lambrecht[SUP] 1 2 9 [/SUP]
Affiliations
Severe COVID-19 is frequently associated with vascular complications, raising ongoing debate about whether SARS-CoV-2 can directly infect endothelial cells and thereby contribute to disease pathogenesis. Although endothelial cells express angiotensin-converting enzyme 2 (ACE2), the in vivo relevance of endothelial-restricted viral tropism remains unclear. To directly assess the consequences of endothelial-restricted SARS-CoV-2 tropism in vivo, we generated a transgenic mouse model expressing human ACE2 under control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2). Despite confirmed pulmonary endothelial expression and protein presence of hACE2, SARS-CoV-2 infection of Cdh5-hACE2 mice did not induce clinical illness, detectable viral replication, immune cell influx in the lung, or histopathological abnormalities in the lung or brain. These findings indicate that endothelial-restricted SARS-CoV-2 tropism alone is insufficient to drive productive infection and clinical disease in vivo, suggesting that endothelial involvement in COVID-19 likely arises in the context of broader cellular infection or systemic host responses rather than from primary endothelial infection.
Importance: Although SARS-CoV-2 primarily infects the upper and lower airways, COVID-19 was quickly recognized as a multi-organ disease, in which vascular complications are a recurring feature. This has raised the possibility that direct infection of endothelial cells contributes to disease pathogenesis. However, whether vascular injury arises from productive endothelial infection or instead represents a secondary consequence of systemic inflammation remains unresolved. To directly disentangle these possibilities and define the in vivo consequences of endothelial-restricted viral tropism, we generated a transgenic mouse model expressing human ACE2 under the control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2).
Keywords: coronavirus; endothelial dysfunction; immunology; mouse model; viral tropism.
. 2026 Aug 11:e0131126.
doi: 10.1128/spectrum.01311-26. Online ahead of print.
Revisiting endothelial tropism of SARS-CoV-2 using a cell-specific hACE2 mouse model
Sahine Lameire[SUP] #[/SUP][SUP] 1 2 [/SUP], Nincy Debeuf[SUP] #[/SUP][SUP] 1 2 [/SUP], Julie Deckers[SUP] 1 2 [/SUP], Caroline De Wolf[SUP] 1 2 [/SUP], Manon Vanheerswynghels[SUP] 1 2 [/SUP], Wendy Toussaint[SUP] 1 2 [/SUP], Lize De Vlieger[SUP] 3 4 [/SUP], Lien Van Hoecke[SUP] 3 4 [/SUP], Arnout Bruggeman[SUP] 3 4 5 [/SUP], Sieglinde De Cae[SUP] 6 7 [/SUP], Bert Schepens[SUP] 6 7 [/SUP], Stijn Vanhee[SUP] 1 2 8 [/SUP], Bart N Lambrecht[SUP] 1 2 9 [/SUP]
Affiliations
- PMID: 42578668
- DOI: 10.1128/spectrum.01311-26
Severe COVID-19 is frequently associated with vascular complications, raising ongoing debate about whether SARS-CoV-2 can directly infect endothelial cells and thereby contribute to disease pathogenesis. Although endothelial cells express angiotensin-converting enzyme 2 (ACE2), the in vivo relevance of endothelial-restricted viral tropism remains unclear. To directly assess the consequences of endothelial-restricted SARS-CoV-2 tropism in vivo, we generated a transgenic mouse model expressing human ACE2 under control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2). Despite confirmed pulmonary endothelial expression and protein presence of hACE2, SARS-CoV-2 infection of Cdh5-hACE2 mice did not induce clinical illness, detectable viral replication, immune cell influx in the lung, or histopathological abnormalities in the lung or brain. These findings indicate that endothelial-restricted SARS-CoV-2 tropism alone is insufficient to drive productive infection and clinical disease in vivo, suggesting that endothelial involvement in COVID-19 likely arises in the context of broader cellular infection or systemic host responses rather than from primary endothelial infection.
Importance: Although SARS-CoV-2 primarily infects the upper and lower airways, COVID-19 was quickly recognized as a multi-organ disease, in which vascular complications are a recurring feature. This has raised the possibility that direct infection of endothelial cells contributes to disease pathogenesis. However, whether vascular injury arises from productive endothelial infection or instead represents a secondary consequence of systemic inflammation remains unresolved. To directly disentangle these possibilities and define the in vivo consequences of endothelial-restricted viral tropism, we generated a transgenic mouse model expressing human ACE2 under the control of the endothelial-specific Cdh5 promoter (Cdh5-hACE2).
Keywords: coronavirus; endothelial dysfunction; immunology; mouse model; viral tropism.