Nasal carriage of S. aureus: host-pathogen interactions

金黄色葡萄球菌的鼻携带：宿主-病原体相互作用

• 批准号: 7046426
• 负责人: ALEXANDER MICHAEL COLE
• 金额: $ 32.18万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046426
• 关键词: Staphylococcus aureus; bactericidal immunity; biofilm; body fluids; clinical research; cysteine endopeptidases; disease carrier state; disease reservoirs; host organism interaction; human subject; lactoferrin; lysozyme; microorganism growth; mucosal immunity; protease inhibitor; proteomics; respiratory epithelium; respiratory system; tear

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.

描述（由申请方提供）：鼻腔携带金黄色葡萄球菌（SA）是使个体易于发生严重医院感染的常见因素，并且是耐药菌株的重要储存库。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鼻携带可能是由于鼻腔流体的先天性抗菌活性受损。发现主要宿主防御多肽脂质运载蛋白-1（细菌铁载体的清道夫）的蛋白质表达水平在来自其鼻腔通道被SA定殖的供体的人鼻液中降低。在抗菌研究中，脂质运载蛋白-1协同溶菌酶在体外杀死SA。最重要的是，脂质运载蛋白-1可以恢复选择性去除阳离子多肽的非载体鼻液的固有抗SA活性，并且通过添加铁可以消除恢复活性。总的来说，我们的研究结果清楚地表明了脂笼蛋白-1缺乏与SA运载的重要相关性。我们假设1）脂质运载蛋白-1的表达在SA携带者的鼻粘膜中失调，有助于SA的进行性定殖，2）纠正脂质运载蛋白-1缺陷将重建SA携带者鼻液对SA分离株的抗微生物活性，和3）SA增强脂质运载蛋白-1和其他宿主防御分子的上皮表达，与非携带者粘膜相比，这有助于SA在携带者粘膜上的优先定殖。为了检验这些假设，我们将：1）表征脂质运载蛋白-1在SA鼻携带中的生物学作用，2）检查细菌和宿主因素对脂质运载蛋白-1的表达和抗SA活性的影响，和3）检查人鼻上皮对SA定殖的贡献。我们提出的研究代表了一种生物学相关的方法，以确定和联系人类气道疾病的致病因素（阳离子多肽抗菌剂）与其影响（SA鼻携带）。 与公共卫生的相关性：SA携带具有越来越重要的临床意义，因为医院获得性感染通常由鼻孔中携带耐药性SA的人传播。我们的研究将表征负责SA携带的因素，并将继续开发一个非常有用的和自然的模型，用于研究细菌与人体易于接触的粘膜表面的相互作用。