BACKGROUND: Infection with the Ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of Ebola haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with Ebola virus. METHODS: We used a rhesus macaque model of Ebola haemorrhagic fever, which produces near 100% mortality. We administered recombinant nematode anticoagulant protein c2 (rNAPc2), a potent inhibitor of tissue factor-initiated blood coagulation, to the macaques either 10 min (n=6) or 24 h (n=3) after a high-dose lethal injection of Ebola virus. Three animals served as untreated Ebola virus-positive controls. Historical controls were also used in some analyses. FINDINGS: Both treatment regimens prolonged survival time, with a 33% survival rate in each treatment group. Survivors are still alive and healthy after 9 months. All but one of the 17 controls died. The mean survival for the six rNAPc2-treated macaques that died was 11.7 days compared with 8.3 days for untreated controls (p=0.0184). rNAPc2 attenuated the coagulation response as evidenced by modulation of various important coagulation factors, including plasma D dimers, which were reduced in nearly all treated animals; less prominent fibrin deposits and intravascular thromboemboli were observed in tissues of some animals that succumbed to Ebola virus. Furthermore, rNAPc2 attenuated the proinflammatory response with lower plasma concentrations of interleukin 6 and monocyte chemoattractant protein-1 (MCP-1) noted in the treated than in the untreated macaques. INTERPRETATION: Post-exposure protection with rNAPc2 against Ebola virus in primates provides a new foundation for therapeutic regimens that target the disease process rather than viral replication.
BACKGROUND: Infection with the Ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of Ebola haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with Ebola virus. METHODS: We used a rhesus macaque model of Ebola haemorrhagic fever, which produces near 100% mortality. We administered recombinant nematode anticoagulant protein c2 (rNAPc2), a potent inhibitor of tissue factor-initiated blood coagulation, to the macaques either 10 min (n=6) or 24 h (n=3) after a high-dose lethal injection of Ebola virus. Three animals served as untreated Ebola virus-positive controls. Historical controls were also used in some analyses. FINDINGS: Both treatment regimens prolonged survival time, with a 33% survival rate in each treatment group. Survivors are still alive and healthy after 9 months. All but one of the 17 controls died. The mean survival for the six rNAPc2-treated macaques that died was 11.7 days compared with 8.3 days for untreated controls (p=0.0184). rNAPc2 attenuated the coagulation response as evidenced by modulation of various important coagulation factors, including plasma D dimers, which were reduced in nearly all treated animals; less prominent fibrin deposits and intravascular thromboemboli were observed in tissues of some animals that succumbed to Ebola virus. Furthermore, rNAPc2 attenuated the proinflammatory response with lower plasma concentrations of interleukin 6 and monocyte chemoattractant protein-1 (MCP-1) noted in the treated than in the untreated macaques. INTERPRETATION: Post-exposure protection with rNAPc2 against Ebola virus in primates provides a new foundation for therapeutic regimens that target the disease process rather than viral replication.
Authors: Xiankun Zeng; Candace D Blancett; Keith A Koistinen; Christopher W Schellhase; Jeremy J Bearss; Sheli R Radoshitzky; Shelley P Honnold; Taylor B Chance; Travis K Warren; Jeffrey W Froude; Kathleen A Cashman; John M Dye; Sina Bavari; Gustavo Palacios; Jens H Kuhn; Mei G Sun Journal: Nat Microbiol Date: 2017-07-17 Impact factor: 17.745
Authors: Anita K McElroy; Bobbie R Erickson; Timothy D Flietstra; Pierre E Rollin; Stuart T Nichol; Jonathan S Towner; Christina F Spiropoulou Journal: J Infect Dis Date: 2014-02-12 Impact factor: 5.226
Authors: Lauren M Smith; Lisa E Hensley; Thomas W Geisbert; Joshua Johnson; Andrea Stossel; Anna Honko; Judy Y Yen; Joan Geisbert; Jason Paragas; Elizabeth Fritz; Gene Olinger; Howard A Young; Kathleen H Rubins; Christopher L Karp Journal: J Infect Dis Date: 2012-12-18 Impact factor: 5.226
Authors: Thomas W Geisbert; Kathleen M Daddario-DiCaprio; Kinola J N Williams; Joan B Geisbert; Anders Leung; Friederike Feldmann; Lisa E Hensley; Heinz Feldmann; Steven M Jones Journal: J Virol Date: 2008-04-02 Impact factor: 5.103
Authors: Peter J Hotez; Paul J Brindley; Jeffrey M Bethony; Charles H King; Edward J Pearce; Julie Jacobson Journal: J Clin Invest Date: 2008-04 Impact factor: 14.808