Laboratory Studies of Abnormal Host Defense and Immunoregulatory Diseases

宿主对贝氏颗粒杆菌防御的研究仍在继续，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氏颗粒杆菌的不寻常脂多糖。 这种材料对人先天免疫系统具有显著的低刺激性，无论是在NADPH氧化酶的弱激活方面还是在细胞因子分泌的弱刺激方面。我们正在与格鲁吉亚大学复杂碳水化合物研究中心的Yossi Shiloach（NIDDK）和Russel Carlson合作，以完成这种生物体的非典型脂多糖（LPS）的纯化和结构表征，并确定它是否作为抗炎抑制性LPS或仅仅是人类免疫系统成分无法识别。 在2014财年，我们启动了几项研究，以评估针对CGD真菌和细菌病原体的新型抗菌剂。 研究正在进行中，以确定铁螯合剂是否可以单独或与免疫细胞一起发挥作用，以限制微生物的生长。 基于以前年度报告中描述的转录组学项目，我们已经测试并确认了几种化合物的抗菌活性，这些化合物抑制与人白细胞相互作用后上调的特定微生物酶。 我们计划在来年测试这些化合物是否可以保护小鼠免受CGD病原体的感染。

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.