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.

项目总结