Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

• Published in: Scientific reports Vol. 13; no. 1; p. 3103
• Main Authors: Nakayama, Takashin, Azegami, Tatsuhiko, Kiso, Maki, Imai, Masaki, Uraki, Ryuta, Hayashi, Kaori, Hishikawa, Akihito, Yoshimoto, Norifumi, Nakamichi, Ran, Sugita-Nishimura, Erina, Yoshida-Hama, Eriko, Kawaoka, Yoshihiro, Itoh, Hiroshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-02-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/590; 692/699/255; Animals; Antibodies, Viral; Body weight; Coronaviruses; COVID-19; COVID-19 vaccines; Disease Models, Animal; Fibrin; Humanities and Social Sciences; Immunization; Immunoglobulin G; Infections; Lipopolysaccharides; Lysis; Mice; Microvasculature; multidisciplinary; Pandemics; Plasminogen Activator Inhibitor 1; Plasminogen activator inhibitors; SARS-CoV-2; Science; Science (multidisciplinary); Sepsis; Severe acute respiratory syndrome coronavirus 2; Survival; Thromboembolism; Thrombosis; Vaccines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-30305-8

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.