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Victoria Wahl-Jensen,
Jennifer A Cann,
Kathleen H Rubins,
John W Huggins,
Robert W Fisher,
Anthony J Johnson,
Fabian de Kok-Mercado, Thomas Larsen,
Jo Lynne Raymond,
Lisa E Hensley,
Peter B Jahrling
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ABSTRACT: Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections - an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions.
PLoS ONE 01/2011; 6(10):e24832. · 4.09 Impact Factor
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ABSTRACT: Zaire Ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to that in humans. During several independent therapy studies, we noted altered tissue tropism in 6 rhesus macaques that survived longer than those with a typical disease course. The mean time to death for these 6 macaques was 21.7 days, which is significantly longer than the average mean time to death of 8.3 days for 20 untreated historical control animals. In addition to living significantly longer, these 6 animals exhibited a variety of deteriorating clinical signs with pathologic findings that were not seen in the untreated control animals, as well as the presence of viral antigen in the brain, eye, pancreas, thyroid, and lung. We suggest that treatment extended the time course of the disease and permitted the virus to infect tissues not usually affected in the typical model.
The Journal of Infectious Diseases 12/2007; 196 Suppl 2:S323-8. · 6.41 Impact Factor
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ABSTRACT: The survival of 7 of 8 patients with Ebola virus (EBOV) infection after transfusions of convalescent-phase blood during a 1995 outbreak of EBOV infection is frequently cited as evidence that passive immunotherapy is a viable treatment option. To test whether whole-blood transfusions were more efficacious than passively administered immunoglobulins or monoclonal antibodies, we transfused convalescent-phase blood from EBOV-immune monkeys into naive animals shortly after challenge with EBOV. Although passively acquired antibody titers comparable to those associated with effective vaccination were obtained, all monkeys that had received transfusions succumbed to infection concurrently with control monkeys. These data cast further doubt on the value of passive immunotherapy for the treatment of EBOV infection.
The Journal of Infectious Diseases 12/2007; 196 Suppl 2:S400-3. · 6.41 Impact Factor
