Brincidofovir

Cardiomyopathy and stroke are major complications of Chagas disease (CD). We investigated if hypercoagulability, endothelial cell (EC) dysfunction, and blood stasis cause cardiac-cerebral fibrinogenesis in CD. C57BL/6 mice infected with Trypanosoma cruzi (Tc) were evaluated at acute (AT), indeterminate (IT), and chronic (CT) stages of CD. Mice were given anti-parasite, bicistronic immunogens (BCV or BCVR) to determine the role of Tc in fibrinogenesis. We monitored (1) platelet and coagulation cascade activation; (2) cardiac-cerebral blood vessels injury; (3) proinflammatory/prothrombotic phenotypes of microglia, macrophages, and vascular cells; and (4) fibrinogenesis. After a quiescent acute phase, plasma levels of coagulation and other factors of platelet activation/aggregation, hypercoagulability, and clotting capacity were increased in IT-CT mice. Proinflammatory and prothrombotic cytokines/chemokines in cardiac-cerebral blood vessels were also significantly increased in IT-CT mice. Loss of cardiac EC and a marked increase in their proinflammatory/cell-adhesion response were not compensated for by a pro-angiogenic/wound-healing response in cardiac-cerebral tissues of infected mice. Microglial proinflammatory activation preceded the vascular inflammation suggesting a feedback cycle of EC activation in brain of infected mice. Treatment with BCV/BCVR controlled the parasite persistence and hypercoagulability/vascular inflammation in infected mice. Importantly, BCV/BCVR treatment abolished the fibrin clots that otherwise were pronounced in heart and brain of IT-CD mice. We conclude that acute Tc infection triggered a subdued hemodynamic disorder, and the persistence of low-grade parasites contributed to a cardiovascular/cerebrovascular proinflammatory and prothrombotic response and fibrin deposition in mice. BCV/BCVR offer potential immunotherapies for reducing the recurrent clot formation and risk of stroke in CD.

Borealpox virus (BRPV) is a zoonotic orthopoxvirus which was first documented in Alaska in 2015. Although most human infections are mild, a recent fatal case in an immunocompromised individual highlights the importance of studying this emerging pathogen. To date, less than 10 human cases of BRPV infection have been confirmed which limit the availability of clinical data on the effectiveness of antiviral therapy. Here, we examined the effectiveness of cidofovir, brincidofovir, and tecovirimat in cell culture and found all three were potent inhibitors of BRPV. In order to further study these modalities in vivo, we assessed immunocompetent and immunodeficient mice as disease models for BRPV. CAST/EiJ mice proved to be a suitable immunocompetent model for BRPV infection with high viral titres in several organs and route-dependent lethality. BRPV infection in immunodeficient mice, including STAT1^-/-, scid, and NSG strains, was uniformly lethal and characterized by high viral titres as well as profuse fluid retention in the peritoneal cavity. Using CAST/EiJ mice, we then evaluated cidofovir, brincidofovir, and tecovirimat therapies. Post-exposure treatment resulted in significant reductions in viral titres and an improved clinical course of infection. Our results demonstrate the utility of mouse models to study the pathogenicity of BRPV and support the use of these antivirals to treat human infections.