We have made the remarkable discovery that a crude bacterial lysate can stimulate the lung innate immune system, resulting in broad protection against pathogenic microorganisms including agents of bioterrorism. Moreover, we have identified a single bacterial protein, EF2505, that has the ability to induce Stimulated Innate Resistance (StIR) to an extent similar to that observed with the crude bacterial lysate. These discoveries represent the basis for the current proposal, the ultimate goal of which is to develop and test a clinically active immunostimulant that can be used to protect against a broad range of microbial bioterror agents. To accomplish this, we have assembled a research team with complimentary expertise in order to determine the molecular mechanisms that cause StIR, which we believe will be required for FDA approval of the product. In addition, we will develop a prototype product and demonstrate its ability to protect against in vivo infections with Bacillus anthracis, Yersinia pestis and Francisella tularensis in mouse models.
|Cleaver, J O; You, D; Michaud, D R et al. (2014) Lung epithelial cells are essential effectors of inducible resistance to pneumonia. Mucosal Immunol 7:78-88|
|Tuvim, Michael J; Gilbert, Brian E; Dickey, Burton F et al. (2012) Synergistic TLR2/6 and TLR9 activation protects mice against lethal influenza pneumonia. PLoS One 7:e30596|
|Evans, Scott E; Tuvim, Michael J; Fox, Cory J et al. (2011) Inhaled innate immune ligands to prevent pneumonia. Br J Pharmacol 163:195-206|
|Duggan, Jeffrey M; You, Dahui; Cleaver, Jeffrey O et al. (2011) Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice. J Immunol 186:5916-26|
|Evans, Scott E; Xu, Yi; Tuvim, Michael J et al. (2010) Inducible innate resistance of lung epithelium to infection. Annu Rev Physiol 72:413-35|
|Evans, Scott E; Scott, Brenton L; Clement, Cecilia G et al. (2010) Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. Am J Respir Cell Mol Biol 42:40-50|