Nasal carriage of S. aureus: host-pathogen interactions

鼻腔携带金黄色葡萄球菌(SA)是一个常见的因素，使个人容易患上严重的 院内感染，是容纳和传播耐药菌株的重要宿主。这个 近四分之一看似健康的人会受到精神障碍的影响，其分子和细胞基础是 未知。我们试点项目的实验表明，SA鼻腔携带可能是由于先天损害 鼻液的抗菌活性。一种主要的宿主防御多肽的蛋白质表达水平， Lipocalin-1(一种细菌铁载体的清除剂)被发现在人的鼻液中被还原。 鼻道被金黄色葡萄球菌定植的供者。在抗菌研究中，Lipocalin-1在 与溶菌酶协同在体外杀死金黄色葡萄球菌。最重要的是，Lipocalin-1可以恢复固有的抗SA 选择性去除阳离子多肽的非载体鼻液的活性及其修复活性 可以通过添加铁来消除。总的来说，我们的发现清楚地表明了一个重要的 Lipocalin-1缺乏与SA携带者的相关性。我们假设1)Lipocalin-1的表达为 SA携带者鼻黏膜调节失调，导致SA进行性定植，2) 纠正Lipocalin-1缺陷将重建SA载体鼻液的抗菌活性 SA分离株，以及3)SA增强上皮细胞Lipocalin-1的表达和其他宿主防御 分子，这有助于SA在载体粘膜上的优先定植 载体粘膜。为了验证这些假说，我们将：1)表征Lipocalin-1在SA中的生物学作用 鼻腔携带，2)检测细菌和宿主因素对表达和抗SA活性的影响 Lipocalin-1的表达，以及3)检测人鼻上皮对SA定植的贡献。我们的建议 研究提出了一种生物学上相关的方法来识别和联系人类呼吸道的致病因素 疾病(阳离子多肽抗菌剂)及其影响(SA鼻腔携带)。 与公共卫生的相关性：SA携带者在临床上越来越重要，因为医院获得了 感染通常由鼻孔携带抗药性金黄色葡萄球菌的人传播。我们的研究将 描述导致SA运输的因素，并将继续开发一个非常有用和自然的模型 用于研究细菌与人类易于接触的粘膜表面的相互作用。

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 non- carrier 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.