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: 10626906
• 负责人: Elizabeth Anne Grice
• 金额: $ 51.63万
• 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/10626906
• 关键词: Acceleration; Adhesions; Alcaligenes; Amputation; Attenuated; Bioinformatics; Biological Markers; Chronic; Classification; Clinical; Coculture Techniques; Complication; Complications of Diabetes Mellitus; Corpus striatum structure; Corynebacterium; Coupling; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Enterococcus faecalis; Environmental Pollutants; Family suidae; Fractionation; Gene Expression; Genetic; Genomic approach; Genomics; Genotype; Grant; Growth; Immune response; Impaired healing; Impaired wound healing; In Vitro; Infection; Intervention; Invaded; Ischemia; Knowledge; Length of Stay; Lower Extremity; 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; 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; machine learning framework; 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; secondary metabolite; 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代价高昂的并发症。微生物定植和 据推测，生物膜的形成会损害伤口愈合并导致严重的并发症，例如 骨髓炎和截肢。尽管所有慢性伤口都定植有微生物群，但其重要性在 是否存在临床感染，目前尚不清楚。在这次竞争性更新中，我们假设主机 反应、伤口愈合和临床 DFU 结果取决于 1) 伤口病原体金黄色葡萄球菌； 2）与伤口病原体的共生相互作用；和 3) 与宿主的共生互动。在上一个周期中，我们开发了鸟枪宏基因组 用于分析定植于神经病性、非感染性 DFU 的微生物群的测序流程（n=100；“DFU100” 队列）在纵向前瞻性队列研究中。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 结局相关。因此，在目标 1 中，我们将使用 微生物基因组方法和来自 DFU100 队列的匹配临床分离株来鉴定金黄色葡萄球菌 DFU 发病机制的基因组决定因素及其与临床结果的关联。我们还观察到 临床上被视为“旁观者”的物种（例如皮肤共生体、环境污染物）影响 伤口病原体的毒力并调整宿主组织修复反应以促进体内愈合。目标2将 确定皮肤共生体纹状棒杆菌是否可以调节金黄色葡萄球菌的毒力并改善 金黄色葡萄球菌伤口感染的小鼠和猪模型中的伤口愈合。目标 3 基于我们的观察 粪产碱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 糖尿病伤口愈合小鼠模型中的伤口闭合。我们将建立机制和治疗 粪曲霉介导的宿主反应的潜力，可加速伤口愈合。拟议的 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群的干预措施以改善结果 利用微生物之间以及宿主之间的相互作用进行治愈； 2) 识别微生物生物标志物 对有并发症风险的患者进行分类。

项目成果

Redefining the Chronic-Wound Microbiome: Fungal Communities Are Prevalent, Dynamic, and Associated with Delayed Healing.

• DOI: 10.1128/mbio.01058-16
• 发表时间: 2016-09-06
• 期刊: mBio
• 影响因子: 6.4
• 作者: Kalan L;Loesche M;Hodkinson BP;Heilmann K;Ruthel G;Gardner SE;Grice EA
• 通讯作者: Grice EA

An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin.

探索 Desemzia incerta 对皮肤上耐甲氧西林金黄色葡萄球菌定植的抵抗机制。

• DOI: 10.1101/2023.10.11.561853
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Wei,Monica;Knight,SimonAb;Fazelinia,Hossein;Spruce,Lynn;Roof,Jennifer;Chu,Emily;Walsh,Jasmine;Flowers,Laurice;Kim,DanielY;Zhu,Jun;Grice,ElizabethA
• 通讯作者: Grice,ElizabethA

Variable staphyloxanthin production by Staphylococcus aureus drives strain-dependent effects on diabetic wound-healing outcomes.

• DOI: 10.1016/j.celrep.2023.113281
• 发表时间: 2023-10-31
• 期刊: Cell reports
• 影响因子: 8.8

Reply to "Understanding the Role of Fungi in Chronic Wounds".

回复“了解真菌在慢性伤口中的作用”。

• DOI: 10.1128/mbio.02033-16
• 发表时间: 2016
• 期刊: mBio
• 影响因子: 6.4
• 作者: Kalan,Lindsay;Gardner,SueE;Grice,ElizabethA
• 通讯作者: Grice,ElizabethA

Insights into the skin microbiome of sickle cell disease leg ulcers.

• DOI: 10.1111/wrr.12924
• 发表时间: 2021-09
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Byeon J;Blizinsky KD;Persaud A;Findley K;Lee JJ;Buscetta AJ;You S;Bittinger K;Minniti CP;Bonham VL;Grice EA
• 通讯作者: Grice EA