Filovirus Pathogenesis in Nonhuman Primates

Abstract

Abstract : Infections with Ebola and Marburg viruses cause severe and fatal hemorrhagic disease in humans and nonhuman primates. While progress to define the mechanisms of filoviral pathogenesis has been made in the last decade, cultural mores, and a range of logistical problems, have hindered the systematic pathogenetic analysis of human filoviral infections. Nonhuman primate models of filoviral hemorrhagic fever (HF) have been developed, but with few exceptions, previous investigations examined animals naturally infected or killed when moribund, and shed little light on the pathogenesis of infection during the period before death. More recently, longitudinal analysis of pathogenetic events in nonhuman primate models of Ebola virus (EBOV) HF have revealed new and important findings. Specifically, tissue factor plays an important role in triggering the hemorrhagic complications that characterize EBOV infections, and dysregulation of protein C exacerbates disease. Moreover, replication of EBOV in endothelial cells was not consistently observed until the latter stages of disease, well after the onset of disseminated intravascular coagulation, suggesting that the characteristic coagulation abnormalities are not the direct result of filoviral-induced cytolysis of endothelial cells. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease course in intravascular as well as extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding suggesting the importance of innate immunity in determining the fate of the host. Accordingly, nonhuman primate models have been invaluable in identifying several new targets for chemotherapeutic interventions that may ameliorate the effects of filoviral HF.