Novel Therapeutic Approach to Invasive Group A Streptococcal Disease

侵袭性 A 组链球菌疾病的新治疗方法

• 批准号: 10452033
• 负责人: Michael G. Caparon
• 金额: $ 23.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-05 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452033
• 关键词: Acids; Address; Adoptive Transfer; Aerobic; Animal Model; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Bacteria; Behavior; Blood Circulation; Cells; Data; Debridement; Disease; Disease Outcome; Endosomes; Enzymes; Equilibrium; Fermentation; Generations; Genetic; Goals; Gram-Positive Bacteria; Growth; Hour; Immune; Immune response; Immunosuppression; In Vitro; Infection; Infectious Skin Diseases; Inflammatory; Interleukin-10; Lactate Dehydrogenase; Lesion; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Necrotizing fasciitis; Operative Surgical Procedures; Oxygen; Pathogenesis; Pathology; Pathway interactions; Perfusion; Pharmacology; Phenocopy; Play; Process; Production; Pyruvate; Pyruvate Metabolism Pathway; Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Soft Tissue Infections; Streptococcus; Streptococcus pyogenes; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment outcome; Ulcer; Validation; Volatile Fatty Acids; arm; attenuation; base; cytokine; disorder control; fatty acid metabolism; improved; in vivo; inhibitor; lactic acid bacteria; limb amputation; macrophage; microbial; mortality; mutant; novel strategies; novel therapeutic intervention; pathogen; prevent; pyruvate dehydrogenase; recruit; response; single-cell RNA sequencing; standard of care; subcutaneous

ABSTRACT Microbial-derived Short Chain Fatty Acids (SCFAs) have emerged as important mediators of “Disease Tolerance,” a process that seeks to limit collateral damage to host tissues that accompanies immune responses. SCFAs are the principle end-products of the metabolism of the Gram-positive pathogen Streptococcus pyogenes which can cause several severe invasive diseases that are notoriously difficult to treat due to extensive and rapid tissue destruction that limits perfusion of antibiotics to the site of bacterial multiplication. For the most severe manifestations, in particular necrotizing fasciitis, lesions expand to involve additional tissue at a rapid rate that can approach several cm per hour. This necessitates multiple rounds of aggressive and disfiguring surgical interventions, including debridement, fasciotomy and even amputation of limbs and this lack of therapeutic options results in high mortality. An important gap in our treatment arsenal is the lack of therapies to mitigate tissue damage during severe invasive disease, which would improve the efficacy of antibiotic treatment to promote clearance of the infection. The goal of this study is to explore proof-of-principle that therapeutic manipulation of streptococcal pyruvate metabolism can provide a viable strategy for mitigation of tissue damage to improve treatment outcomes of severe, invasive S. pyogenes disease. This concept builds upon our preliminary data that suggests S. pyogenes employs its several alternative pathways for pyruvate reduction to actively manipulate the host’s “Disease Tolerance” response to promote its ability to infect diverse host niches. Disease tolerance is the process the host employs to balance pathogen growth against the collateral damage to host tissues that accompanies immune responses, known as Growth/Damage Balance. Through identification of host cells and relevant signaling pathways that control disease tolerance, a therapeutic approach that targets microbial metabolic and host cell signaling pathways can reduce damage to tissue to improve the ability of antibiotics to clear infections.

摘要