Ebola virus and the related Marburg virus are members of the Filovirus family, which are pleomorphic, negative-sense RNA viruses whose genome organization is most similar to the Paramyxoviridae. Of the four identified strains of Ebola virus, three—the Zaire, Ivory Coast, and Sudan strains—have been shown to cause disease in both humans and nonhuman primates, with the Zaire strain exhibiting the highest lethality rate (13, 29). The only documented outbreaks of Ebola virus infection in the United States were fortunately restricted to nonhuman primates at holding facilities in Virginia and Texas, caused by the Reston strain, which has not yet caused fatal disease in humans (19).

The Ebola virus GP is synthesized in a secreted (sGP) or full-length transmembrane form, and each gene product has distinct biochemical and biological properties. For example, GP appears to form a trimeric complex (30) and binds preferentially to endothelial cells, whereas sGP does not (49). Preferential binding of Ebola virus GP to the endothelium was demonstrated by use of two independent methodologies as follows: direct binding was assessed by fluorescence-activated cell sorter analysis, and pseudotyping experiments were performed in which virus titers, cell numbers, and confluence were carefully determined so that the multiplicity of infection was controlled and equal in all cell types. Another study failed to demonstrate this preferential binding (17), but direct binding of GP to endothelial cells was not measured and neither the multiplicity of infection, target cell numbers, nor cell confluence was reported in that study. The receptors required for cell binding and infection are not completely understood. A folate-related receptor can serve as a cofactor to facilitate infection (8), but whether it serves as a receptor remains unclear. The cell surface lectin DC-SIGN can also facilitate GP binding to cells through viral carbohydrate determinants, but it does not appear to mediate entry by itself (1, 32). In contrast to GP, sGP gives rise to a dimeric protein (30) that interacts with neutrophils (49). sGP mediates neutrophil binding, directly or indirectly, through CD16b, the neutrophil-specific form of the Fcγ receptor III (49). After the initial description of the neutrophil binding of sGP, it was shown that immunoglobulin G (IgG), but not an Fab fragment, against sGP was needed to detect neutrophil binding (T. Maruyama, M. J. Buchmeier, P. W. H. I. Parren, and D. R. Burton, Technical Comment, Science 282:843-844, 1998). A subsequent study showed that the binding could also be seen if an irrelevant IgG was used with the Fab fragment against sGP (Z.-Y. Yang, R. Delgado, L. Xu, R. F. Todd, E. G. Nabel, A. Sanchez, and G. J. Nabel, Author's Reply, Science 282:844-846, 1998). Though such binding could potentially arise from binding of immune complexes, additional studies using resonance energy transfer showed that neutrophils incubated with sGP showed a significant reduction in the CR3-Fcγ RIIIB RET signal (22), demonstrating that sGP alters the physical and functional interaction between Fcγ RIIIB and CR3. Through this interaction, sGP may contribute to immune evasion by inhibiting early steps in neutrophil activation (as measured by the down-modulation of l-selectin) that would ordinarily assist in virus clearance (49).

Ebola virus replicates at an unusually high rate that overwhelms the protein synthesis apparatus of infected cells and host immune defenses (28). Both the adaptive immune and inflammatory systems respond to infection at the same time that some cell types, specifically monocytes and macrophages, are targets relevant to disease pathogenesis. This feature of the infection was initially suggested by the immunohistochemical localization of Ebola virus in vivo: endothelial cells, mononuclear phagocytes, and hepatocytes are the main targets of infection (3, 4, 12, 50).

Several animal models have been developed to study the pathogenesis of Ebola virus infection and to assess the efficacy of various vaccine approaches. Guinea pigs and nonhuman primates represent the primary animal models for vaccine development because the progression and pathogenesis most closely resemble those of the human disease (10,46, 47). A murine model was later developed by serial passage of virus in mice (7). Though the model allows the use of knockout and inbred strains to evaluate genetic determinants of disease, it is considered less predictive of human disease because it relies on a serially passaged, attenuated virus. While symptoms and time course of disease in guinea pigs parallel those in humans, nonhuman primate infection is considered the most predictive and useful for vaccine development (14).