During the first award period the MRCE Aerosol Biology/Small Animal Models Core D (Core D) supported smallpox disease research (using ectromelia, monkeypox, and vaccinia viruses) as this disease was one of the most intensely modeled in Region 7. With licensure of Modified Vaccinia Ankara (MVA) and the availability of ACAM 2000¿ (derived from Dryvax¿), and phase I clinical trials of orthopoxvirus antivirals, ST-246 and CMX001, there is a diminishing need for in vivo testing of additional orthopoxvirus therapeutics and prophylactics. There is, however, still much to learn concerning the innate immune response to orthopxviruses and other infectious agents. The capacity of Core D to create additional models for use in basic research and prophylactic and therapeutic efficacy testing was under-scored by the development of the following five lethal challenge models: influenza virus A in C57BL/6-sfaH"A mice, monkeypox virus (MPXV) in C57BL/6-sfaf1"A mice and dormice, SARS-CoV in immunosuppressed hamsters, and B. anthracis in the A/J mice. Importantly, additional assays were implemented that characterized in greater detail disease progression (temperature by telemetry and blood levels of alanine aminotransferase (ALT) and virus genome equivalents) and the host response to infection (cytokines, NK cells, granulocytes, monocytes, and antigen specific CD4* and CD8+ T cells). Although Core D is capable of infecting animals through a full range of inoculation routes, it provides exceptional support for the use of respiratory routes of infection. The Core also has the capacity to aerosolize and deliver therapeutics to the respiratory tract for the study of early intervention strategies. The Core is one of the few academic facilities in the country to have the capacity to test therapeutics and prophylactics in compliance with GLP standards. Additional Core D services include: animal acquisition, protocol development, Institutional Animal Care and Use Committee (IACUC) protocol review, Institutional Biosafety committee (IBC) protocol review, health surveillance, husbandry, specimen collection, surgical services, clinical laboratory sample analysis, histology services, and report writing. Specific Aim 1. Develop for investigators in the Regional Centers of Excellence small animal respiratory challenge models for Category A-C Priority pathogens and emerging infectious disease agents Specific Aim 2: Carry out respiratory small animal challenges and provide investigators with designated specimens, tissues and/or cells from small animals infected with various agents Specific Aim 3: Support preclinical testing of therapeutics and prophylactics for Category A-C Priority pathogens and emerging infectious disease agents

This work will facilitate the development of prophylactics and therapeutics for bacterial and viral agents that could potentially be used as bioterrorist weapons.