Spotted Fever group Rickettsia are the etiologic agents of astoundingly dangerous acute bacterial infections like Rocky Mountain spotted fever, Rickettsia parkeri rickettsiosis and Murine Typhus. Once transmitted to a human by an infected arthropod, the intracellular Rickettsia grow within the endothelial lining of blood vessels. Within a few days of infection, the bacteria parasitize the entire vascular system causing vascular leakage, hypovolemia and pervasive multiorgan failure. While rapid diagnosis and treatment with the single applicable antibiotic has improved overall prognosis, this strategy has only decreased fatality rates to 5-10% of cases. The Rickettsia have evolved the ability to “steal” and coat the bacterial surface with the mammalian complement regulator Factor H (FH) so that the complement system loses the ability to efficiently detect and attack the pathogen. On a molecular level, this interaction involves a bacterial surface protein and a common “bacteria-association” region of FH called short consensus repeats 19-20 (SCR19-20). We are developing proteins that fuse SCR19-20 to the fragment crystallizable region (Fc) of human IgG3. So, when the bacteria try to “steal” FH using SCR19-20, they do not acquire the complement-protective properties of FH. Instead, these bacteria are coated with IgG3 Fc which results in activation of a plethora of immunoprotective mechanisms, including complement activation, FcR-mediated phagocytosis, steric inhibition and antibody-dependent intracellular neutralization. This novel strategy for anti-infective development is the foundation of our proposal. We have already demonstrated that multiple Rickettsia species bind our immunotherapeutic fusion protein, Fc3/SCR(19-20), and this interaction leads to a severe reduction in bacterial viability. Using the current protein Fc3/SCR(19-20) as a foundation, we will generate additional protein variants designed to decrease off-target host binding, increase phagocytosis and harness antibody-dependent intracellular neutralization. These proteins will be produced using our proprietary expression platform and extensively purified. Fc3/SCR(19-20) and all new derivatives will be examined for complement activation, complement-mediated killing, opsonophagocytosis by macrophages and interaction with the intracellular antibody sensor TRIM21. Those proteins that possess the greatest potential will be further examined for protective capacity in small animal models of Rickettsia infection. Completion of this Phase I proposal will result in a lead compound that possess the desired antimicrobial properties, laying the groundwork for developing a Fc3/SCR(19-20) variant as a treatment or post tick bite prophylactic for rickettsial diseases in humans.