Abstract Body (Do not enter title and authors here): Background: Preceding respiratory tract infections (RTI) due to bacteria or virus has been linked to an increasing risk of stroke likely by potentiating an inflammatory immune response, endothelial dysfunction, platelet activation, and coagulopathy. Von Willebrand factor (VWF) plays a crucial role in hemostasis and thrombosis by promoting platelet adhesion to the subendothelial matrix and factor VIII stabilization. VWF activity is regulated by the protease ADAMTS13. Prior population-based studies suggest increased VWF levels and reduced ADAMTS13 activity as independent risk factors for stroke; however, a causal role of the VWF/ADAMTS13 axis in RTI-mediated stroke exacerbation is not investigated yet.
Objective: To determine the causal role of the VWF/ADAMTS13 axis in a mouse model of preceding RTI and ischemic stroke.
Methods: Wild-type (WT) mice were infected intranasally with sub-lethal doses of S. aureus or vehicle on days 0, 2, and 5. On day 6, infection was measured in the lungs (MRI), brain, and blood. VWF levels and ADTMTS13 activity were quantified by ELISA in the plasma on day 6 post-infection. In another set of experiments, on day 6 post-infection S. aureus-infected WT, Vwf^-/-, Adamts13^-/- mice were subjected to transient (30 min) middle cerebral artery ischemia using a filament model. Functional outcomes (modified neurological severity score, rota-rod, corner, novel object recognition, and wire-hanging test) were measured in the same cohort of mice up to 4 weeks.
Result: We demonstrate that a sustained S. aureus infection localized to lungs in WT mice, increases plasma VWF levels (~2-fold) and reduces ADAMTS13 activity that were associated with larger infarcts and worsened long-term functional outcomes (P<0.05 vs. mock-infected mice). S. aureus infected VWF-deficient mice exhibited reduced infarcts and better long-term functional outcomes (P <0.05 vs. S. aureus infected WT). In contrast, S. aureus infected ADAMTS13-deficient mice exhibited larger infarcts and worse long-term functional outcomes (P <0.05 vs. S. aureus infected WT).
Conclusion: In a model of respiratory tract infection during the week preceding stroke, VWF has a causal role in worsening stroke outcomes while ADAMTS13 is protective.