Biofilms and Immunity in Chronic Wounds

描述（由申请人提供）：本申请旨在解决慢性伤口中细菌定植和持久性的影响。生物膜的形成显然与慢性和持续性细菌感染有关。这大大延迟和复杂化伤口愈合。与通常由宿主清除的急性细菌感染不同，与生物膜相关的慢性感染即使使用高剂量抗生素和完整的免疫系统也不容易解决。细菌性病原体铜绿假单胞菌和金黄色葡萄球菌是本应用的重点，它们引起一系列与生物膜相关的临床疾病，包括持续性气道感染、烧伤感染、心内膜炎和手术部位感染。未解决的感染伤口也有助于医院的持续存在和细菌在卫生保健机构的传播。由于生物膜形成导致的慢性感染的丰富和持续，导致了生物膜部署定向机制来破坏宿主免疫系统的识别、激活和功能的假设。这项建议将使用最先进的分子和基因组方法来更好地了解细菌定植在慢性伤口中的影响。目的1将确定铜绿假单胞菌和金黄色葡萄球菌抵抗宿主源性抗菌剂和先天免疫细胞杀伤的机制。目的2将利用新开发的猪全层烧伤慢性创面模型和烧伤创面清创后的人体组织来研究铜绿假单胞菌和金黄色葡萄球菌引起的生物膜持续性感染。慢性感染模型的发展，可以随着时间的推移采样，以及获得来自人类烧伤创面损伤的材料，为检查宿主生物膜形成的影响提供了一种相关的、独特的和新颖的方法。从体外数据得出的结论将在猪模型和人体组织中进行有效的测试，以适用于临床感染。最终，收集到的信息将有助于治疗一系列慢性感染，包括高度流行的持续性伤口感染。

DESCRIPTION (provided by applicant): This application seeks to address the impact of bacterial colonization and persistence in chronic wounds. The formation of biofilms has clearly been linked to chronic and persistent bacterial infections. This considerably delays and complicates wound healing. Unlike acute bacterial infections, which are often cleared by the host, biofilm-related chronic infections are not easily resolved even with high dose antibiotics and intact immunity. The bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus, which are the focus of this application, cause an array of biofilm-related clinical diseases including persistent airway infections, burn wound infections, endocarditis, and surgical site infections. Unresolved infected wounds also contribute to nosocomial persistence and the spread of bacteria in health care settings. The abundance and persistence of chronic infections due to biofilm formation has led to the hypothesis that biofilms deploy directed mechanisms to subvert recognition, activation, and functions of the host immune system. This proposal will use state-of-the- art molecular and genomic approaches to better understand the impact of bacterial colonization in chronic wounds. Aim 1 will define mechanisms by which P. aeruginosa and S. aureus resist killing by host-derived antimicrobials and innate immune cells. Aim 2 will utilize a newly developed porcine full thickness burn chronic wound model and explanted human tissue from burn wound debridement to investigate biofilm persistent infections caused by P. aeruginosa and S. aureus. The development of a chronic infection model that can be sampled over time as well as access to materials derived from humans suffering burn-wound injury provides a relevant, unique, and novel approach for examining the effects of biofilm formation in the host. Conclusions made from in vitro data will be efficiently tested in the porcine model and human tissue for applicability in clinical infection. Ultimately information gathered will aid the treatment of an array of chronic infections including highly prevalent persistent wound infections. PUBLIC HEALTH RELEVANCE: Pseudomonas aeruginosa and Staphylococcus aureus are versatile opportunistic pathogens that can cause devastating persistent wound infections. Within the wound, these organisms transform into a resistant community called a biofilm. Biofilm-related chronic infections are not easily resolved even with high dose antibiotics and intact immunity. This application will use molecular and genomic approaches to define how biofilm-growing bacteria resist antibiotics and host immune cells. This will allow us to better understand the impact of bacterial colonization in chronic wounds and aid future management and treatment of chronic infections that significantly impact human health.