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

基本信息

批准号：
7326788
负责人：
ALEXANDER MICHAEL COLE
金额：
$ 30.65万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
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/7326788
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

项目摘要

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.

鼻腔携带金黄色葡萄球菌 (SA) 是使个体易患严重疾病的常见因素院内感染，并且是隐藏和传播耐药菌株的重要储存库。这这种疾病影响了近四分之一表面健康的人，其分子和细胞基础是未知。我们的试点项目的实验表明，SA 鼻运输可能是由于先天受损造成的鼻液的抗菌活性。主要宿主防御多肽的蛋白质表达水平， lipocalin-1（细菌铁载体的清除剂）被发现在人鼻液中减少鼻腔通道被 SA 定植的捐赠者。在抗菌研究中，lipocalin-1 发挥作用与溶菌酶协同作用，在体外杀死SA。最重要的是，lipocalin-1 可以恢复内在的抗 SA 选择性去除阳离子多肽的非载体鼻液的活性以及恢复活性可以通过添加铁来消除。总的来说，我们的研究结果清楚地表明了一个重要的 lipocalin-1 缺乏与 SA 携带的相关性。我们假设 1) lipocalin-1 的表达是 SA 携带者鼻粘膜失调，导致 SA 逐渐定植，2) 纠正 lipocalin-1 缺陷将重建 SA 载体鼻液的抗菌活性 SA 分离株，3) SA 增强 lipocalin-1 和其他宿主防御的上皮表达分子，与非分子相比，这有助于 SA 在载体粘膜上优先定植载体粘膜。为了检验这些假设，我们将： 1) 表征 lipocalin-1 在 SA 中的生物学作用鼻腔运输，2）检查细菌和宿主因素对表达和抗SA活性的影响 lipocalin-1 和 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 携带的临床重要性日益增加，因为医院获得性感染感染通常是由鼻孔中携带抗生素耐药性 SA 的人传播的。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且自然的模型用于研究细菌与人体容易接触的粘膜表面的相互作用。