The most worrisome infectious agents of bioterrorism would be disseminated as aerosols to the lungs. Lunginnate immune responses are unique, primarily driven by an immunoregulatory program that minimizesinflammatory damage in the alveoli caused by the daily bombardment of inhaled particles. A critical mediatorof immunity in this environment is the alveolar macrophage. For airborne infectious agents, the lung appearsto be relatively incompetent in controlling early microbial growth, particularly in the case of intracellularpathogens of macrophages. Most targeted infectious agents of bioterrorism are intracellular pathogens,including Francisella tularensis (Ft). We describe a GLRCE Research Project that will dissect criticalelements of the macrophage innate immune response to virulent Ft using in vitro and in vivo models. Theprojects will focus on the 1) molecular determinants of phagocytosis of Ft and their regulation by lungcollectins and other macrophage C-type lectins; 2) characterization of the interactions of Ft with intracellularpathogen recognition molecules termed CATERPILLAR proteins that are lined to the macrophageinflammasome; 3) characterization of key macrophage biochemical pathways activated by Ft that regulateinflammatory responses; and 4) macrophage responses and pathogenesis related to novel Ft acidphosphatases. The goal of the program is to gain a clearer understanding of Ft pathogenesis and lungimmune responses to Ft, especially as they relate to macrophages, which will be critical in identifyingmolecular targets for new diagnostic strategies as well as targeted immune therapies aimed at enhancinghost immunity in the lung., This program will complement established programs in the GLRCE and the LungBiology BSL III Core program at The Ohio State University.
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