Development of nonhuman primate model of S. aureus nasal carriage

金黄色葡萄球菌鼻携带非人灵长类动物模型的开发

基本信息

批准号：
8953176
负责人：
ALEXANDER MICHAEL COLE
金额：
$ 26.14万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-16 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8953176
关键词：
AIDS/HIV problem Acute Adhesives Affect Animal Model Animals Anterior nares Anti-Bacterial Agents Bacteria Binding Proteins Biological Biology Carrier State Cells Cessation of life Chronic Clinical Clinical Trials Communities Development Disease Epithelial Epithelial Cells Experimental Models Fibronectins Genes Genotype Growth Host Defense Human Human Activities Immune response In Vitro Individual Integration Host Factors Interleukin-1 Investigation Liquid substance Macaca Macaca nemestrina Mediating Modeling Monkeys Mucous Membrane Mupirocin Mus Natural Immunity Nose Nosocomial Infections Outcome Participant Phase Primates Proteomics Recovery Reporting Research Role Sequence Homology Staphylococcus aureus Structure of mucous membrane of nose Study models Surface Surveys Testing Tissue Model Tissues Washington Work antimicrobial base clinically relevant cohort cost effective genetic analysis in vivo inflammatory marker killings microbial model development nonhuman primate pathogen polypeptide public health relevance response safety testing

项目摘要

DESCRIPTION (provided by applicant): Staphylococcus aureus (SA) nasal carriage is a common condition that predisposes individuals to severe community-acquired and nosocomial infections, and acts as an important reservoir for spreading pathogenic strains. We are beginning to understand that host and bacterial determinants collectively contribute to the carrier state, and have utilized nasal epithelial cells and ex vivo tissue models of the upper airways to better define the role of bacterial and host determinants of SA nasal carriage. However, to confirm the in vivo role of these factors in nasal carriage, a suitable animal model of SA colonization would be required. While useful, murine models are not ideal for studying longterm SA nasal carriage or the host's response to colonization, since these animals are not naturally colonized by SA, extraordinarily high inocula result only in transient colonization, and murine noses poorly model the mucosal host response of human noses. Thus, current models do not afford the ability to test SA carriage in its natural state. Nonhuman primates would likely better serve to model human SA nasal carriage. We explored whether pigtailed macaques could be used as a biologically relevant model of experimental SA nasal colonization, and discovered that over half were nasally colonized by SA. Genetic analyses revealed sequence homology between nasal SA of humans and macaques, suggesting that pigtailed macaque noses could be experimentally colonized with human-derived SA strains. This proposal seeks to develop a tractable, cost-effective model of nasal carriage of SA in pigtailed macaques, and utilize the model to assess the host's mucosal response to SA colonization. In Aim 1, we will develop the pigtailed macaque nasal carriage model using each macaque's own SA nasal isolate, and then use the model to explore how clinically relevant nasal human SA strains colonize macaque noses. Following experimental nasal colonization with macaque and clinically relevant nasal human SA strains, level of carriage will be assessed for two months by quantifying bacterial load and genotyping the recovered SA to confirm whether colonization persists with the inoculated strains. In Aim 2, we will utilize the pigtailed macaque model to determine how nasal carriage of SA affects innate mucosal host defense in vivo. Given we have reported that nasal fluids from human carriers of SA are deficient in killing SA in vitro, we will determine whether nasal fluids from macaques that carry SA in their noses are similarly deficient before and after in vivo experimental SA colonization. We will also utilize a robust proteomic approach to evaluate the biological effect of experimental SA colonization on the expression of antimicrobial polypeptides, inflammatory markers, and other mucosal host defense components. Collectively, we would provide the field with a nonhuman primate model for studying determinants of SA nasal carriage, and testing the safety and efficacy of candidate anti-SA nasal prophylaxes.

描述（由适用提供）：金黄色葡萄球菌（SA）鼻携带者是一种常见的疾病，使人容易受到严重的社区性和医生感染，并且是传播致病菌株的重要储层。我们开始了解到，宿主和细菌统称为载体状态做出了贡献，并利用了上呼吸道的鼻皮细胞和离体组织模型，以更好地定义细菌和宿主的作用，并确定SA鼻滚子的作用。但是，要确认这些因素在鼻携带中的体内作用，这是一个合适的动物模型需要殖民化。尽管有用，但鼠模型并不是研究长期SA鼻载体或宿主对定殖的反应的理想选择，因为这些动物不是由SA自然地殖民的，因此仅会导致瞬时定植，而鼠鼻子却很差地模拟了人类鼻子的粘膜宿主反应。这就是当前的模型无法实现其自然状态测试SA载体的能力。非人类的私人可能会更好地对人类鼻载体进行建模。我们探索了辫子的猕猴是否可以用作实验性SA鼻定植的生物学相关模型，并发现超过一半的SA被SA鼻腔定植。遗传分析揭示了人类和猕猴鼻SA之间的序列同源性，这表明可以用人来源的SA菌株在实验上扎根猕猴的鼻子。该提案旨在开发一种在辫子猕猴中的鼻鼻运输的可疗法，具有成本效益的模型，并利用该模型来评估宿主对SA定植的粘膜反应。在AIM 1中，我们将使用每个猕猴自己的SA鼻分离株开发锯齿状的猕猴鼻滚子模型，然后使用该模型探索临床上相关的鼻腔SA菌株如何定居猕猴鼻子。在用猕猴和临床相关的鼻部人类SA菌株进行实验性鼻腔定殖后，将通过量化细菌负荷和基因分型来评估两个月的运输水平，以确认定植是否持续到接种菌株中。在AIM 2中，我们将利用辫子的猕猴模型来确定SA的鼻携带者如何影响天生粘膜宿主在体内的防御。鉴于我们报告说，来自SA的人类载体的鼻液缺乏体外杀死SA的鼻腔，我们将确定来自猕猴的鼻液是否在其鼻子中携带SA的鼻液同样缺乏，在此之前和之后体内实验SA定植。我们还将利用一种强大的蛋白质组学方法来评估实验SA定植对抗菌多肽，炎症标记和其他粘膜宿主防御成分表达的生物学作用。总的来说，我们将为该领域提供一个非人类的私人模型，用于研究SA鼻弹架的决定师，并测试候选抗SA鼻鼻腔预防的安全性和有效性。