Nasal carriage of S. aureus: host-pathogen interactions

描述（由申请人提供）：金黄色葡萄球菌（SA）的鼻腔携带是使个体容易发生严重医院感染的常见因素，并且是耐药菌株窝藏和传播的重要宿主。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。我们的试点项目的实验表明，SA的鼻腔携带可能是由于鼻腔液体的先天抗菌活性受损。一种主要的宿主防御多肽，脂钙素-1（细菌铁载体的清道夫）的蛋白表达水平在被SA定植的人鼻液中被发现降低。在抗菌研究中，脂钙素-1与溶菌酶协同作用，在体外杀死SA。最重要的是，脂钙素-1可以恢复选择性丧失阳离子多肽的非载体鼻液固有的抗sa活性，而这种恢复活性可以通过添加铁而被消除。总的来说，我们的研究结果清楚地表明，脂钙素-1缺乏与SA携带有重要的相关性。我们推测：1)在SA携带者的鼻黏膜中，脂钙素-1的表达失调，导致SA的逐渐定植；2)纠正脂钙素-1缺失将重建SA携带者鼻液对SA分离株的抗菌活性；3)SA增加了脂钙素-1和其他宿主防御分子的上皮表达，这有助于SA在载体粘膜上比非载体粘膜上优先定植。为了验证这些假设，我们将：1)表征脂钙素-1在SA鼻腔携带中的生物学作用，2)检查细菌和宿主因素对脂钙素-1表达和抗SA活性的影响，以及3)检查人鼻上皮对SA定植的贡献。我们提出的研究代表了一种生物学相关的方法来识别和联系人类气道疾病的致病因素（阳离子多肽抗菌剂）及其影响（SA鼻载）。

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.