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

Abstract

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.

PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age

“…Further, lack of PAI-1 was particularly deleterious in aged mice, but had little effect on young mice highlighting the importance of age as a biological variable in studies with rodents. Most prior studies reporting a deleterious role for PAI-1 were conducted on young mice using a non-infectious endotoxemia model ( Murakami et al, 1997 ; Gupta et al, 2015 ; Nakayama et al, 2023 ).…”

“…Prior work emphasizing a deleterious role for PAI-1 in AKI showed that young mice lacking PAI-1 have increased survival, improved kidney function, decreased apoptosis, reduced inflammation, attenuated fibrin deposition in the kidneys, and increased levels of circulating activated protein C as compared to WT mice after LPS challenge ( Gupta et al, 2015 ; Nakayama et al, 2023 ). These benefits were similarly observed in a mutant mouse model where the interaction between PAI-1 and vitronectin was abolished, verifying a key role for this interaction in mediating PAI-1’s effects on the kidney ( Gupta et al, 2015 ).…”

“…These benefits were similarly observed in a mutant mouse model where the interaction between PAI-1 and vitronectin was abolished, verifying a key role for this interaction in mediating PAI-1’s effects on the kidney ( Gupta et al, 2015 ). In contrast, there was no benefit of PAI-1 inhibition in mice with SARS-CoV-2 infection ( Nakayama et al, 2023 ). This could indicate that the beneficial effects of reducing PAI-1 are an LPS-specific phenomenon and occur in the absence of true infection.…”

“…We previously reported that circulating plasma levels of PAI-1 are associated with acute kidney injury (AKI) in two different cohorts of patients (surgical intra-abdominal sepsis patients and heterogeneous critically ill patients with sepsis-associated AKI) ( Zwischenberger et al, 2021 ) and in mice with cecal-slurry induced sepsis ( Bruno et al, 2022 ). Other murine studies have provided a mechanistic link between PAI-1, sepsis severity, and AKI; however, these have been limited to endotoxemia models with young mice ( Gupta et al, 2015 ; Nakayama et al, 2023 ). The goal of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis.…”