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.

抽象的 微生物衍生的短链脂肪酸 (SCFA) 已成为重要的介质 “疾病耐受性”是一个旨在限制对宿主组织造成附带损害的过程 SCFA 是免疫反应的主要终产物。 革兰氏阳性病原体化脓性链球菌，可引起多种严重的侵袭性感染 由于广泛而快速的组织破坏而导致的众所周知难以治疗的疾病 对于最严重的情况，限制抗生素灌注到细菌繁殖部位。 表现，特别是坏死性筋膜炎，病变扩大到累及其他组织 速度快到每小时几厘米，这需要多轮攻击。 以及毁容外科手术，包括清创术、筋膜切开术，甚至截肢术 肢体和治疗选择的缺乏导致了我们的高死亡率。 治疗手段是缺乏减轻严重侵袭性组织损伤的治疗方法 疾病，这将提高抗生素治疗的功效，促进清除 本研究的目的是探索治疗操作的原理验证。 链球菌丙酮酸代谢可以为减轻组织损伤提供可行的策略 改善严重的侵袭性化脓性链球菌疾病的治疗效果。 根据我们的初步数据，表明化脓性链球菌利用其几种替代途径 丙酮酸减少积极操纵宿主的“疾病耐受性”反应以促进 它感染不同宿主生态位的能力是宿主用来进行疾病耐受的过程。 平衡病原体的生长与免疫伴随的对宿主组织的附带损害 通过识别宿主细胞和相关的反应，称为生长/损伤平衡。 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通路可以减少对组织的损伤，提高 抗生素清除感染。