Investigating the role of Staphylococcus aureus strain-level diversity on neutrophil recruitment and wound healing in a cutaneous leishmaniasis infection

研究皮肤利什曼病感染中金黄色葡萄球菌菌株水平多样性对中性粒细胞募集和伤口愈合的作用

• 批准号: 10313240
• 负责人: Victoria Lovins
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313240
• 关键词: Amputation; Antibodies; Automobile Driving; Bacteria; Biological Markers; Biopsy; Cells; Chronic; Classification; Clinical; Cutaneous; Cutaneous Leishmaniasis; Data; Disease; Down-Regulation; Epithelial; Epithelial Cells; Failure; Gene Activation; Gene Expression; Genes; Genome; Human; Impaired healing; Impaired wound healing; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-8; Leishmania; Leishmania major; Leishmaniasis; Lesion; Measures; Mediating; Messenger RNA; Metadata; Microbe; Migration Assay; Modeling; Mus; Neutrophil Infiltration; Osteomyelitis; Outcome; Parasite Control; Parasites; Parasitic infection; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Phenotype; Phylogenetic Analysis; Process; Proteins; Prunella vulgaris; Quality of life; Reporter; Research; Resolution; Role; Sepsis; Severities; Site; Skin; Skin Tissue; Skin injury; Skin wound healing; Soft Tissue Infections; Staphylococcus aureus; Staphylococcus aureus infection; Testing; Time; Tissues; Tumor-infiltrating immune cells; Virulence; Work; Wound Infection; Wound models; chronic wound; comparative genomics; cytokine; diabetic ulcer; differential expression; genome sequencing; healing; immunopathology; in vivo; insight; keratinocyte; microbial; microbiota; migration; mortality; mouse model; neutrophil; new therapeutic target; novel; pathogen; response; skin lesion; skin microbiome; skin microbiota; transcriptome sequencing; whole genome; wound; wound healing

PROJECT SUMMARY Cutaneous leishmaniasis is a parasitic infection that causes a variable spectrum of disease ranging from single, self-healing lesions to disfiguring chronic lesions that do not heal despite treatment. While the factors driving lesion chronicity are not clear, it is evident that many of the most severe forms of the disease are caused by uncontrolled inflammation rather than high parasite burden. In mice, chronic leishmaniasis lesions are characterized by increased neutrophil accumulation, persistent activation of inflammatory cytokines, and increased infiltration of immune cells to the lesion site, all of which exacerbate tissue damage and delay healing. Our lab has previously shown that colonizing microbes on the skin contribute to immunopathology in murine models, however the role of the skin microbiota in regulating lesion healing is not known. We have found that the most common bacteria colonizing human cutaneous leishmania lesions is Staphylococcus aureus (S. aureus) which delays wound healing in a strain-specific manner across many different pathologies and is a potent neutrophil recruiter. We have also been able to show that S. aureus clinical isolates cultured from human cutaneous leishmaniasis lesions induce secretion of different amounts of neutrophil chemotactic factors such as interleukin-8 (IL-8) by epithelial cells in a wound setting. Therefore, the central hypothesis of my proposal is that S. aureus delays cutaneous leishmaniasis lesion healing through strain-variable neutrophil recruitment and accumulation. In Aim 1, I will determine the strain-specific effect of S. aureus-mediated neutrophil recruitment on wound healing and immunopathology in both a wounding model and in a cutaneous leishmaniasis model using LysM-EGFP mice. In Aim 2, I will identify differences S. aureus neutrophil recruitment and persistence genes across clinical isolates using whole genome sequencing and comparative genomics and associate this data with clinical outcomes and RNA sequencing gene expression from human cutaneous leishmaniasis lesions. These findings will collectively drive understanding of the strain-specific effects of S. aureus infection and neutrophil recruitment on wound healing, uncover biomarkers that can be used to predict patient outcome, and identify novel therapeutic targets in the treatment of cutaneous leishmaniasis.

项目摘要 皮肤利什曼病是一种寄生虫感染，引起多种疾病， 从单一的自愈性损伤到尽管治疗也不愈合的毁容性慢性损伤。虽然这些因素 驱动病变慢性化尚不清楚，很明显，许多最严重的疾病形式是由 而不是高寄生虫负担。在小鼠中，慢性利什曼病病变是 其特征在于增加的中性粒细胞积聚、炎性细胞因子的持续活化，以及 免疫细胞向病变部位的浸润增加，所有这些都会加剧组织损伤并延迟愈合。 我们的实验室先前已经表明，皮肤上的定植微生物有助于小鼠的免疫病理学。 然而，皮肤微生物群在调节损伤愈合中的作用尚不清楚。我们发现 定植于人类皮肤利什曼原虫病损的最常见细菌是金黄色葡萄球菌（S. 金黄色葡萄球菌），其在许多不同的病理学中以菌株特异性方式延迟伤口愈合，并且是一种有效的 中性粒细胞募集者。我们也可以证明S。人培养的金黄色葡萄球菌临床分离株 皮肤利什曼病损害诱导分泌不同量的中性粒细胞趋化因子 白细胞介素-8（IL-8）在伤口环境中通过上皮细胞表达。因此，我的建议的核心假设是， S.金黄色葡萄球菌通过应变可变中性粒细胞募集延迟皮肤利什曼病病变愈合， 积累在目标1中，我将确定S.金黄色介导的中性粒细胞募集 在创伤模型和皮肤利什曼病模型中对创伤愈合和免疫病理学的影响 使用LysM-EGFP小鼠。在目标2中，我将确定差异S。金黄色中性粒细胞募集和持续存在 使用全基因组测序和比较基因组学， 人类皮肤利什曼病病变的临床结果和RNA测序基因表达数据。 这些发现将共同推动人们对S.金黄色葡萄球菌感染， 中性粒细胞募集对伤口愈合的影响，揭示可用于预测患者结局的生物标志物，以及 确定治疗皮肤利什曼病的新的治疗靶点。