Laboratory Studies of Abnormal Host Defense and Immunoregulatory Diseases

宿主对贝塞斯致密颗粒杆菌的防御研究仍在继续，特别关注基因组和表型水平上的菌株特异性差异。在2014财年，我们继续研究来自贝塞斯致密颗粒杆菌的不寻常的脂多糖。这种物质对人先天免疫系统有明显的低刺激作用，包括NADPH氧化酶的弱激活和细胞因子分泌的弱刺激。我们正在与佐治亚大学复合碳水化合物研究中心的Yossi Shiloach （NIDDK）和Russel Carlson合作，完成该生物的非典型脂多糖（LPS）的纯化和结构表征，并确定它是作为抗炎抑制LPS还是仅仅是人类免疫系统成分无法识别的。

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.