Immunotherapy to combat skin infections

免疫疗法对抗皮肤感染

• 批准号: 9906450
• 负责人: Soman N Abraham
• 金额: $ 27.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-23 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906450
• 关键词: Adjuvant; Affect; Amines; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Blood Circulation; Burn injury; Cells; Cessation of life; Clinical; Coupled; Cytoplasmic Granules; Data; Dendritic Cells; Dermal; Dermis; Development; Diabetes Mellitus; Environment; Exhibits; Explosion; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Immune; Immune system; Immunotherapeutic agent; Immunotherapy; Infection; Infectious Skin Diseases; Lesion; Location; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mucous Membrane; Multiple Bacterial Drug Resistance; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Patients; Peptide Hydrolases; Peptides; Play; Population; Postoperative Period; Process; Resistance; Resolution; Role; Site; Skin; Skin wound; Specificity; Staphylococcus aureus; Sterility; Superbug; Surface; Surgical wound; Time; Tissues; Topical application; Vaccines; Wild Type Mouse; Work; Wound Healing; adaptive immune response; bacterial resistance; chemokine; combat; cost; cytokine; diabetic patient; healing; healthcare-associated infections; injured; interest; mast cell; mastoparan; neutrophil; pathogen; recruit; success

Abstract Surgical site infections occurring post-operatively are the single largest cause of healthcare- associated infections, affecting 157,500 patients in the US and costing billions of dollars annually. With the rapid emergence of multi-resistance among bacteria infecting the skin, including the growing population of diabetic patients, and with no new antibiotics coming down the pipeline, there is a dire clinical need for alternate strategies to combat skin infections. In view of the recent successes of immunotherapy in curing several lethal cancers, coopting the host's own immune system to combat skin infections is a viable possibility. We reasoned that a potential target of immunotherapy in the skin are mast cells (MCs). Indeed, we have found that MCs in the skin can contribute to bacterial clearance through the recruitment of MCs. Recently we discovered that a subset of dendritic cells found in close proximity to MCs in the dermis play a key role in wound healing by inducing rapid reepithelization of injured skin. Since wound healing follows bacterial clearance from infected skin, we hypothesis that these dendritic cells may contribute to wound healing following MC activation. We have previously demonstrated that mast cell activators (MCAs) are powerful and safe adjuvants when combined with various vaccines. Here, we have hypothesized that applying the same MCAs to infected skin would accelerate bacterial clearance and wound healing even without the use of antibiotics. To validate these ideas and extend our studies we propose the following: (i) investigate the multifaceted role of MCs and dendritic cells in promoting bacterial clearance and wound healing and (ii) Investigate the use of MCAs in promoting clearance of bacteria and wound healing following infection by several prominent skin pathogens and establishing the underlying basis for this protection.

摘要 术后发生的手术部位感染是医疗保健的最大单一原因- 相关感染，影响美国157，500名患者，耗资数十亿美元 每年。随着感染皮肤的细菌迅速出现多重耐药性， 包括糖尿病患者人数的不断增长，而且没有新的抗生素出现 在管道中，迫切需要替代策略来对抗皮肤感染。在 鉴于最近免疫疗法在治愈几种致命癌症方面取得的成功， 宿主自身的免疫系统对抗皮肤感染是一种可行的可能性。我们推断， 皮肤中免疫治疗的潜在靶点是肥大细胞（MC）。我们发现， 皮肤中的MC可以通过募集MC来促进细菌清除。最近 我们发现，在真皮中与MC非常接近的树突状细胞亚群， 通过诱导受伤皮肤的快速上皮再生而在伤口愈合中起关键作用。自伤 愈合后，细菌清除感染的皮肤，我们假设，这些树突状细胞， 可能有助于MC激活后的伤口愈合。我们之前已经证明， 肥大细胞激活剂（MCAs）在与各种佐剂组合时是有效且安全的佐剂， 疫苗。在这里，我们假设将相同的MCAs应用于受感染的皮肤， 加速细菌清除和伤口愈合，即使不使用抗生素。到 验证这些想法，并扩展我们的研究，我们提出以下建议：（一）调查 MC和树突状细胞在促进细菌清除和伤口愈合中的多方面作用 和（ii）研究MCAs在促进细菌清除和伤口愈合中的用途 在几种主要皮肤病原体感染后， 为了这种保护。