Laboratory Studies of Abnormal Host Defense and Immunoregulatory Diseases

关于寄主对颗粒状芽孢杆菌致密性的研究仍在继续，尤其关注基因组和表型水平上的菌株特异性差异。在2014财年，我们继续对颗粒状杆菌中不寻常的脂多糖进行研究。这种材料对人类先天免疫系统具有显著的低刺激作用，无论是NADPH氧化酶的弱激活还是对细胞因子分泌的弱刺激都是如此。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，完成这种生物的非典型内毒素(LPS)的纯化和结构表征，并确定它是作为抗炎抑制内毒素发挥作用，还是仅仅是人类免疫系统组件不能识别的。 在2014财年，我们启动了几项研究，以评估新型抗菌剂对CGD真菌和细菌病原体的作用。目前正在进行研究，以确定铁络合剂是否可以单独或与免疫细胞共同作用，以限制微生物的生长。根据以前的年度报告中描述的转录项目，我们已经测试并确认了几种化合物的抗菌活性，这些化合物抑制了特定的微生物酶，这些酶在与人类白细胞相互作用时上调。我们计划在未来一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.