The filoviruses and arenaviruses are NIAID/CDC Category A biodefense pathogens that cause severe and rapidly progressing hemorrhagic fever. There are currently no FDA-approved, specific therapeutics against any of these viruses. Investigators in this consortium have recently demonstrated that monoclonal antibodies can provide effective post-exposure protection against these viruses in two or more animal models. Provision of monoclonal antibody immunotherapeutics provides the most economically viable and scientifically proven avenue for pre- or post-exposure therapy. In the armamentarium of this consortium are hundreds of mAbs against these viruses, representing the largest array of antibodies against these viruses yet compiled and including the most effective antibodies known against these viruses. However, we do not what the epitopes of most of these antibodies are, how they function to ameliorate viral infection, or if the currently chosen cocktails are even synergistic. Further, it is largely unknown what sites of the viral glycoproteins are the best targets for antibody intervention. In order to develop these antibodies or cocktails of antibodies for clinical use, we must understand where each antibody binds, which bind to the same or different sites, and which are synergistic and why. This Core (Core D, Mechanistic Structural Biology) will answer these critical knowledge gaps. In this Gore, we are using innovative, state-of-the-art, high-throughput approaches that will allow structural mapping of -100 antibody binding sites per year by single particle electron microscopy. Using these approaches, we will be able to map the epitopes of nearly every anti-filovirus and antiarenavirus antibody known. We will complement these EM approaches by higher-resolution X-ray crystallographic analysis of a smaller set of antibodies of very high interest, chosen for their unique functional capacity and highest efficacy. This information will be used to sort antibodies into groups based on binding site and function. By sorting antibodies into binding site groups, and by integrating essential functional information from the complementary Mechanistic Virology Gore (Core C), we will be able to sort and rank antibodies of each type. We will be able to select the most effective antibodies that bind to each site and determine which combinations among them are most effective. The innovative and state-of-the-art structural studies in this Core will provide information critical to selection and development of the necessary cocktails of antibodies against these emerging and re-emerging public health threats.