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: 7149148
• 负责人: ALEXANDER MICHAEL COLE
• 金额: $ 31.24万
• 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/7149148
• 关键词: Affect; Anterior nares; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Apical; Bacteria; Biological; Biological Markers; Chronic; Clinical; Development; Disease; Epithelial; Epithelial Cells; Fright; Host Defense; Human; Immunologist; In Vitro; Individual; Integration Host Factors; Iron; Lactoferrin; Link; Liquid substance; Microbial Biofilms; Molecular; Mucous Membrane; Muramidase; Nasal Epithelium; Nose; Nosocomial Infections; Peptides; Pharmaceutical Preparations; Pilot Projects; Predisposing Factor; Protein Overexpression; Proteins; Proteomics; Public Health; Research Personnel; Resistance; Role; Shapes; Siderophores; Source; Staphylococcus aureus; Structure of mucous membrane of nose; Study models; Surface; Testing; Time; Work; antimicrobial; base; comparative; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; killings; lipocalin 1; methicillin resistant Staphylococcus aureus; novel; novel strategies; pathogen; polypeptide; prevent; programs; protein expression; reconstitution; research study

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（由申请人提供）：金黄色葡萄球菌（SA）的鼻腔运输是一种常见因素，使人容易患上严重的医院感染，并且是藏有和扩散抗性菌株的重要储层。该疾病影响了将近四分之一健康的人，其分子和细胞碱是未知的。我们的试点项目的实验表明，SA鼻腔运输可能是由于鼻液的先天抗菌活性受损。发现主要宿主防御多肽lipocalin-1（对细菌铁载体的清除剂）的蛋白质表达水平在人类鼻液中的供体中降低了，其鼻通道被SA定居。在抗菌研究中，Lipocalin-1与溶菌酶在体外杀死SA。最重要的是，Lipocalin-1可以恢复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。在总体中，我们的发现清楚地表明了Lipocalin-1缺乏症与SA运输的重要相关性。 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与非载体粘膜相比，SA在载体粘膜上的优先定殖有助于。为了检验这些假设，我们将：1）表征Lipocalin-1在SA鼻弹子中的生物学作用，2）检查细菌和宿主因子对Lipococalin-1的表达和抗SA活性的影响，以及3）检查人类鼻表属对SA共同化的贡献。我们提出的研究代表了一种与生物学相关的方法，用于识别和联系人类气道疾病（阳离子多肽抗菌剂）及其作用（SA鼻纳西式运输）。 与公共卫生有关：SA运输的临床重要性越来越重要，因为医院获得的感染通常是在鼻孔中携带抗抗生素的SA的人传播的。我们的研究将表征负责SA运输的因素，并将继续开发一个非常有用的自然模型，用于研究细菌与人类易于访问的粘膜表面的相互作用。