Nasal carriage of S. aureus: host-pathogen interactions

描述(申请人提供)：鼻腔携带金黄色葡萄球菌(SA)是一种常见的因素，使个人容易受到严重的医院感染，并作为一个重要的储存和传播耐药菌株。这种疾病影响了近四分之一表面上健康的人，其分子和细胞基础尚不清楚。我们试点项目的实验表明，SA鼻腔携带可能是由于鼻液的先天抗菌活性受损所致。一种主要的宿主防御多肽Lipocalin-1(细菌铁载体的清除剂)在SA定植鼻道的供体鼻液中的蛋白表达水平被发现降低。在抗菌研究中，Lipocalin-1与溶菌酶在体外协同作用杀死金黄色葡萄球菌。最重要的是，Lipocalin-1可以恢复选择性去除阳离子多肽的非载体鼻液固有的抗SA活性，这种恢复活性可以被铁的加入所消除。总体而言，我们的研究结果清楚地表明，Lipocalin-1缺乏与SA携带有重要关联。我们推测：1)SA携带者鼻黏膜中Lipocalin-1的表达异常，有助于SA的进行性定植；2)纠正Lipocalin-1缺陷将重建SA载体鼻液对SA分离株的抗菌活性；3)SA上调Lipocalin-1和其他宿主防御分子在鼻黏膜上的表达，这有助于SA在载体黏膜上的优先定植。为了验证这些假设，我们将：1)表征Lipocalin-1在SA鼻腔携带中的生物学作用；2)检测细菌和宿主因素对Lipocalin-1表达和抗SA活性的影响；3)检测人鼻上皮对SA定植的贡献。我们建议的研究代表了一种生物学上的相关方法，以识别和联系人类呼吸道疾病的致病因素(阳离子多肽抗菌剂)及其影响(SA鼻腔携带)。 与公共卫生相关：SA携带者的临床重要性与日俱增，因为医院获得性感染通常是由鼻孔携带抗药性SA的人传播的。我们的研究将表征导致金黄色葡萄球菌携带的因素，并将继续开发一个非常有用和自然的模型来研究细菌与人类易于接触的粘膜表面的相互作用。

DESCRIPTION (provided by applicant): Nasal carriage of Staphylococcus aureus (SA) is a common factor that predisposes individuals to severe nosocomial infections, and acts as an important reservoir for harboring and spreading resistant strains. The disorder affects nearly a quarter of apparently healthy people and its molecular and cellular bases are unknown. Experiments from our pilot project revealed that SA nasal carriage may be due to impaired innate antimicrobial activity of nasal fluid. The protein expression levels of a major host defense polypeptide, lipocalin-1 (a scavenger of bacterial siderophores), was found to be reduced in human nasal fluid from donors whose nasal passageways were colonized by SA. In antibacterial studies, lipocalin-1 worked in concert with lysozyme to kill SA in vitro. Most importantly, lipocalin-1 could restore the intrinsic anti-SA activity of non-carrier nasal fluid selectively depleted of cationic polypeptides, and the restorative activity could be abolished by the addition of iron. In the aggregate, our findings clearly suggest an important correlation of lipocalin-1 deficiency with SA carriage. We hypothesize that 1) the expression of lipocalin-1 is dysregulated in the nasal mucosa of SA carriers, contributing to the progressive colonization of SA, 2) correcting the lipocalin-1 deficiency will reconstitute the antimicrobial activity of SA carrier nasal fluid against isolates of SA, and 3) SA augments the epithelial expression of lipocalin-1 and other host defense molecules, which contributes to preferential colonization of SA on carrier mucosa as compared with noncarrier mucosa. To test these hypotheses, we will: 1) Characterize the biological role of lipocalin-1 in SA nasal carriage, 2) Examine the influence of bacterial and host factors on the expression and anti-SA activity of lipocalin-1, and 3) Examine the contribution of human nasal epithelium to SA colonization. Our proposed studies represent a biologically relevant approach to identify and link causative factors of human airway disease (cationic polypeptide antimicrobials) with their effects (SA nasal carriage). Relevance to Public Health: SA carriage is of increasing clinical importance because hospital-acquired infections are commonly spread by people who carry antibiotic-resistant SA in their nostrils. Our studies will characterize factors responsible for SA carriage, and will continue to develop a very useful and natural model for studying the interactions of bacteria with a readily accessible mucosal surface in humans.