Abstract Body: Background: Preceding respiratory tract infections (RTIs) caused by bacteria or viruses are associated with worse stroke outcomes, likely due to an exaggerated inflammatory immune response, endothelial dysfunction, platelet activation, and coagulopathy. Recent studies have revealed increased plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 activity (the risk factors for stroke) in patients with RTIs, including COVID-19. However, it remains unclear whether an imbalance in the VWF–ADAMTS13 axis plays a causative role in the pathophysiology of S. aureus- or COVID-19-associated stroke severity or is merely an associative marker of disease status.
Objective: To examine whether an imbalance in the VWF–ADAMTS13 axis is a causal link between RTIs and stroke severity.
Methods: Wild-type (WT) mice (3–4 months old) were infected intranasally with sublethal doses of S. aureus (on days 0, 2, and 5) or mouse-adapted SARS-CoV-2 (on day 0). On day 6 (S. aureus) or day 3 (SARS-CoV-2), the infection was confirmed to be localized in the lungs (but not in the brain) and the plasma VWF levels and ADTMTS13 activity were quantified. In another set of experiments, WT, Vwf ^−/−, and Adamts13^−/− mice (3–4 months old) with respective littermate controls were subjected to transient (30 or 45 min) cerebral ischemia (filament stroke model) followed by reperfusion. For the S. aureus experiments, brain infarcts were assessed on day 2 post-reperfusion and functional outcomes (corner test, wire hanging test, modified neurological severity score, and rotarod test) on week 1 and 4 post-reperfusion. For the SARS-CoV-2 experiments, brain infarcts and functional outcomes (the Bederson score) were assessed on day 1 post-reperfusion.
Result: We demonstrated that S. aureus or SARS-CoV-2 infection localized to the lungs in the WT mice resulted in increased (2–3 fold) plasma VWF levels and reduced ADAMTS13 activity, concomitant with larger infarcts and worse functional outcomes (P<0.05 vs. mock-infected mice) up to day 28 post-reperfusion. S. aureus- or SARS-CoV-2-infected VWF-deficient mice exhibited reduced infarcts and improved functional outcomes (P<0.05 vs. infected Vwf^+/+). In contrast, S. aureus or SARS-CoV-2-infected ADAMTS13-deficient mice displayed greater stroke severity (P<0.05 vs. infected Adamts13^+/+).
Conclusion: In the experimental models of RTI preceding stroke, VWF plays a causal role in worsening stroke outcomes, while ADAMTS13 is protective.