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 微生物衍生的短链脂肪酸(SCFA)已成为 “疾病耐受性”，这一过程寻求限制对宿主组织的附带损害， 伴随着免疫反应。单链脂肪酸是植物体内代谢的主要最终产物。 可导致几种严重侵袭性疾病的革兰氏阳性病原菌化脓性链球菌 由于广泛和快速的组织破坏而出了名的难以治疗的疾病， 限制抗生素在细菌繁殖部位的灌流。对于最严重的 临床表现，尤其是坏死性筋膜炎，皮损扩大至累及额外组织。 速度很快，可以接近每小时几厘米。这需要多轮的攻击性 和毁容的外科干预，包括清创，筋膜切开术，甚至截肢 这种缺乏治疗选择的情况导致高死亡率。我们的一个重要差距是 治疗武器库是在严重侵袭期间缺乏减轻组织损伤的治疗方法 疾病，这将提高抗生素治疗的疗效，促进疾病的清除 感染。这项研究的目的是探索治疗手法的原则证明 链球菌丙酮酸代谢可为减轻组织损伤提供一种可行的策略 改善严重侵袭性化脓性链球菌病的治疗结果。这个概念建立在 根据我们的初步数据显示，化脓性链球菌使用了几种替代途径 丙酮酸还原主动操控宿主“耐病”反应促进 它能够感染不同的宿主利基。疾病耐受性是宿主利用的过程 平衡病原体生长与伴随免疫的宿主组织的附带损害 反应，称为生长/损害平衡。通过对宿主细胞的鉴定和相关 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，以提高 清除感染的抗生素。