Studies of host defenses against Granulibacter bethesdensis continue, with particular attention to the strain-specific differences at the genomic and phenotypic levels. During FY14, we continued our studies of the unusual lipopolysaccharide from Granulibacter bethesdensis. This material is remarkably hypostimulatory of the human innate immune system, both in terms of weak activation of the NADPH oxidase and poor stimulation of cytokine secretion. We are collaborating with Yossi Shiloach (NIDDK) and Russel Carlson of the University of Georgia Complex Carbohydrate Research Center to complete the purification and structural characterization of the atypical lipopolysaccharide (LPS) of this organism and determine whether it acts as an anti-inflammatory inhibitory LPS or is merely unrecognized by human immune system components. During FY14, we initiated several studies to evaluate novel antimicrobial agents against CGD fungal and bacterial pathogens. Studies are underway to determine whether iron chelators can act alone or in concert with immune cells to limit microbial growth. Based on transcriptomic projects described in previous annual reports, we have tested and confirmed antibacterial activity of several compounds that inhibit specific microbial enzymes that are upregulated upon interaction with human leukocytes. We plan to test whether these compounds can protect mice from infection by CGD pathogens in the coming year.