Decoding the microbial burden in diabetic foot ulcers

解读糖尿病足溃疡的微生物负荷

• 批准号: 10159971
• 负责人: Elizabeth Anne Grice
• 金额: $ 51.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159971
• 关键词: Adhesions; Alcaligenes; Amputation; Attenuated; Bioinformatics; Biological Markers; Chronic; Clinical; Coculture Techniques; Complication; Complications of Diabetes Mellitus; Corpus striatum structure; Corynebacterium; Coupling; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Enterococcus faecalis; Environmental Pollution; Family suidae; Fractionation; Gene Expression; Genetic; Genomic approach; Genomics; Genotype; Grant; Growth; Immune response; Impaired healing; Impaired wound healing; In Vitro; Infection; Intervention; Knowledge; Lead; Length of Stay; Lower Extremity; Machine Learning; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Metadata; Microbe; Microbial Biofilms; Modeling; Mus; Neuropathy; Osteomyelitis; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Production; Prospective cohort study; Research; Risk; Role; Series; Shotguns; Skin; Staphylococcus aureus; Staphylococcus aureus infection; Techniques; Testing; Therapeutic; Toxic effect; United States; Variant; Virulence; Wound Infection; Wound models; antimicrobial; base; chronic wound; clinically relevant; cohort; comparative; cost; cytokine; diabetic ulcer; diabetic wound healing; foot; genome analysis; genome sequencing; genome wide association study; healing; improved; improved outcome; in vivo; keratinocyte; malignant breast neoplasm; metagenomic sequencing; microbial; microbial colonization; microbial genomics; microbiota; microorganism interaction; migration; mortality; mouse model; non-healing wounds; novel; pathogen; phenotypic data; porcine model; predict clinical outcome; predictive marker; response; tissue repair; tissue-repair responses; transcriptome sequencing; whole genome; wound; wound closure; wound healing

Chronic, non-healing wounds are common and costly complications of diabetes. Microbial colonization and biofilm formation are hypothesized to impair wound healing and contribute to severe complications such as osteomyelitis and amputation. Although all chronic wounds are colonized with microbiota, its importance, in the absence of clinical infection, is currently unknown. In this competitive renewal, we hypothesize that host response, wound healing, and clinical DFU outcomes are determined by 1) genomic diversification of the wound pathogen Staphylococcus aureus; 2) commensal interactions with wound pathogens; and 3) commensal interactions with the host. In the previous cycle, we developed a shotgun metagenomic sequencing pipeline to analyze the microbiota colonizing neuropathic, non-infected DFU (n=100; the “DFU100” cohort) in a longitudinal prospective cohort study. We observed that strain-level variation of the wound pathogen Staphylococcus aureus was associated with DFU outcomes. Therefore, in Aim 1, we will use a microbial genomic approach and matched clinical isolates from the DFU100 cohort to identify S. aureus genomic determinants of pathogenesis in DFU and their association with clinical outcomes. We also observed that species clinically regarded as “bystanders” (e.g. skin commensals, environmental contaminants) influence the virulence of wound pathogens and tune host tissue repair responses to promote healing in vivo. Aim 2 will determine if a skin commensal, Corynebacterium striatum, tunes the virulence of S. aureus and improves wound healing in murine and porcine models of S. aureus wound infection. Aim 3 is based on our observation that Alcaligenes faecalis wound isolates promote keratinocyte migration, cytokine secretion, and accelerated wound closure in a murine model of diabetic wound healing. We will establish the mechanism and therapeutic potential of A. faecalis-mediated host responses that lead to accelerated wound healing. The proposed research will use cutting-edge, cross-disciplinary approaches to investigate interactions between wound pathogens, wound “bystanders”, and the host; understanding these mechanisms will lead to improved DFU outcomes as our long-term objectives are to 1) develop novel microbiota-based interventions to improve healing that exploit microbial interactions with each other and the host; and 2) identify microbial biomarkers to classify patients at risk of complication.

慢性、不愈合的伤口是糖尿病常见且昂贵的并发症。微生物定殖和 假设生物膜形成损害伤口愈合并导致严重的并发症， 骨髓炎和截肢。尽管所有慢性伤口都被微生物群定殖，但其重要性， 目前尚不清楚是否存在临床感染。在这个竞争性的更新中，我们假设主机 反应、伤口愈合和临床DFU结果由以下因素决定：1） 伤口病原体金黄色葡萄球菌; 2）与伤口病原体的体液相互作用;以及3） 与宿主的互动。在上一个周期中，我们开发了一个鸟枪宏基因组 测序管道，以分析定殖神经性、未感染DFU的微生物群（n=100;“DFU 100” 队列）进行纵向前瞻性队列研究。我们观察到伤口的应变水平变化 病原体金黄色葡萄球菌与DFU结果相关。因此，在目标1中，我们将使用 微生物基因组方法和来自DFU 100队列的匹配临床分离株鉴定S.金黄色 DFU发病机制的基因组决定因素及其与临床结局的相关性。我们还观察到 临床上被视为“旁观者”的种属（例如皮肤寄生虫、环境污染物）影响 伤口病原体的毒力和调节宿主组织修复反应以促进体内愈合。目标2将 确定是否一个皮肤寄生虫，棒状杆菌纹状体，调谐的毒力S。金黄色葡萄球菌和改善 小鼠和猪S.金黄色葡萄球菌伤口感染目标3基于我们的观察 粪产碱杆菌伤口分离物促进角质形成细胞迁移、细胞因子分泌并加速 糖尿病伤口愈合的鼠模型中的伤口闭合。我们将建立机制和治疗 A的潜力。粪便介导的宿主反应，导致加速伤口愈合。拟议 研究将使用尖端的跨学科方法来调查伤口之间的相互作用， 病原体、伤口“旁观者”和宿主;了解这些机制将有助于改善DFU 我们的长期目标是：1）开发新的基于微生物的干预措施， 利用微生物与彼此和宿主的相互作用的愈合;和2）鉴定微生物生物标志物， 对有并发症风险的患者进行分类。