PB1078 - Links between coagulation signaling in viral infection and autoimmunity

Background: G-protein coupled protease activated receptors (PARs) are cleaved by coagulation proteases and connect hemostasis with the innate immune response. We have recently shown that coagulation FVIIa interacting with tissue factor (TF) can be synthesized by monocytes/macrophages and regulates nucleic acid sensing through biased PAR2 signaling. Moreover, in latent murine cytomegalovirus (mCMV) infection, TF cytoplasmic domain signaling induces anti-phospholipid-antibodies (aPLs), which promote thrombosis and inflammation and can persist in other autoimmune diseases. However, the roles of immune cell-expressed FVIIa in viral infections are unknown.

Aims: We aimed to elucidate the contributions of myeloid cell-expressed FVIIa to the acute cytokine response of viral infection and the development in aPLs.

Methods: Mice with cell-type specific deletion of the endothelial protein C receptor (EPCR) and FVII were infected with mCMV. We determined plasma cytokines, blood cell counts, and aPL reactivity during acute and latent phases of the infection. We compared these data with the pharmacological intervention using the TF-FVIIa inhibitor NAPc2.

Results: Myeloid expression of FVII and EPCR did not affect blood cell counts, and EPCR deletion did not significantly alter cytokines in the blood. However, in mice lacking FVII in myeloid cells certain proinflammatory cytokines were increased. Purified macrophages lacking EPCR or FVII also secreted reduced levels of IFNα, which is required for aPL development. Accordingly, both LBPA- and β2GPI-reactive antibodies were significantly reduced 5 and 12 weeks after mCMV infection in mice with myeloid deletion of FVII and EPCR compared to littermate controls. This reduction was also achieved by treating infected mice with NAPc2 during the acute infection.

Conclusion(s): These results identify monocyte/macrophage autonomous synthesis of FVII and EPCR as a driver for aPL development in latent viral infection and provide evidence that targeted intervention of TF-FVIIa with NAPc2 could be a promising therapeutic option for suppressing autoimmune pathologies associated with viral infections.