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 微生物来源的短链脂肪酸（SCFA）已成为重要的介导剂， “疾病耐受性”是一个试图限制对宿主组织的附带损害的过程， 伴随着免疫反应。SCFA是代谢的主要终产物， 革兰氏阳性病原体化脓性链球菌可引起几种严重侵袭性 由于广泛和快速的组织破坏， 限制了抗生素在细菌增殖部位的灌注。应付最严峻的 表现，特别是坏死性筋膜炎，病变扩大到涉及额外的组织， 速度很快，可以达到每小时几厘米。这需要多轮积极的 和毁容的外科手术，包括清创术，筋膜切开术，甚至截肢， 这种治疗选择的缺乏导致高死亡率。一个重要的差距，在我们的 治疗武器库是缺乏治疗，以减轻组织损伤，在严重的侵入性 疾病，这将提高抗生素治疗的疗效，以促进清除 感染本研究的目的是探讨原则的证明，治疗操作的 链球菌丙酮酸代谢可提供减轻组织损伤的可行策略 以改善严重、侵袭性链球菌的治疗结果。化脓性疾病这个概念建立在 根据我们的初步数据表明S.化脓性链球菌利用其几种替代途径， 丙酮酸减少，以积极操纵宿主的“疾病耐受性”反应， 它能够感染不同的宿主生态位。疾病耐受性是宿主用来 平衡病原体生长和伴随免疫的宿主组织的附带损害 这就是所谓的增长/损害平衡。通过鉴定宿主细胞和相关的 控制疾病耐受性的信号通路，一种针对微生物的治疗方法 代谢和宿主细胞信号传导途径可以减少对组织的损伤，以提高 抗生素来清除感染。