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
基本信息
- 批准号:10452033
- 负责人:
- 金额:$ 23.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcidsAddressAdoptive TransferAerobicAnimal ModelAnti-Inflammatory AgentsAntibiotic TherapyAntibioticsBacteriaBehaviorBlood CirculationCellsDataDebridementDiseaseDisease OutcomeEndosomesEnzymesEquilibriumFermentationGenerationsGeneticGoalsGram-Positive BacteriaGrowthHourImmuneImmune responseImmunosuppressionIn VitroInfectionInfectious Skin DiseasesInflammatoryInterleukin-10Lactate DehydrogenaseLesionMediator of activation proteinMetabolicMetabolic PathwayMetabolismModelingMusNecrotizing fasciitisOperative Surgical ProceduresOxygenPathogenesisPathologyPathway interactionsPerfusionPharmacologyPhenocopyPlayProcessProductionPyruvatePyruvate Metabolism PathwayRoleSeverity of illnessSignal PathwaySignal TransductionSiteSoft Tissue InfectionsStreptococcusStreptococcus pyogenesTestingTherapeuticTherapeutic InterventionTissuesTreatment outcomeUlcerValidationVolatile Fatty Acidsarmattenuationbasecytokinedisorder controlfatty acid metabolismimprovedin vivoinhibitorlactic acid bacterialimb amputationmacrophagemicrobialmortalitymutantnovel strategiesnovel therapeutic interventionpathogenpreventpyruvate dehydrogenaserecruitresponsesingle-cell RNA sequencingstandard of caresubcutaneous
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michael G. Caparon其他文献
Volatile profiling distinguishes emStreptococcus pyogenes/em from other respiratory streptococcal species
挥发性分析区分化脓性链球菌和其他呼吸道链球菌物种
- DOI:
10.1128/msphere.00194-23 - 发表时间:
2023-09-28 - 期刊:
- 影响因子:3.100
- 作者:
Amalia Z. Berna;Joseph A. Merriman;Leah Mellett;Danealle K. Parchment;Michael G. Caparon;Audrey R. Odom John;Jacqueline M. Achkar - 通讯作者:
Jacqueline M. Achkar
Streptococcus pyogenes protein F promotes invasion of HeLa cells.
化脓性链球菌蛋白 F 促进 HeLa 细胞的侵袭。
- DOI:
10.1099/00221287-144-11-3079 - 发表时间:
1998 - 期刊:
- 影响因子:1.5
- 作者:
Nobuhiko Okada;lchiro Tatsuno;Emanuel Hanski;Michael G. Caparon;C. Sasakawa - 通讯作者:
C. Sasakawa
Reprogramming aerobic metabolism mitigates Streptococcus pyogenes tissue damage in a mouse necrotizing skin infection model
在小鼠坏死性皮肤感染模型中,重新编程有氧代谢可减轻化脓性链球菌组织损伤。
- DOI:
10.1038/s41467-025-57348-x - 发表时间:
2025-03-15 - 期刊:
- 影响因子:15.700
- 作者:
Wei Xu;Tara R. Bradstreet;Zongsen Zou;Suzanne Hickerson;Yuan Zhou;Hongwu He;Brian T. Edelson;Michael G. Caparon - 通讯作者:
Michael G. Caparon
MP23-19 FIBRINOGEN DEPOSITS ON URINARY CATHETERS IN A TIME-DEPENDENT MATTER AND CO-LOCALIZES WITH <em>E. FAECALIS</em> IN PATIENTS WITH POSITIVE <em>E. FAECALIS</em> URINE CULTURES
- DOI:
10.1016/j.juro.2017.02.747 - 发表时间:
2017-04-01 - 期刊:
- 影响因子:
- 作者:
Tyler M. Bauman;Aaron M. Potretzke;Ana L. Flores-Mireles;Jennifer N. Walker;Alyssa M. Park;Henry L. Schreiber;Jerome S. Pinkner;Michael G. Caparon;Scott J. Hultgren;Alana Desai - 通讯作者:
Alana Desai
Michael G. Caparon的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michael G. Caparon', 18)}}的其他基金
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:
10546470 - 财政年份:2022
- 资助金额:
$ 23.63万 - 项目类别:
Characterization of assembly factors for type IV secretion systems
IV 型分泌系统组装因子的表征
- 批准号:
10435561 - 财政年份:2021
- 资助金额:
$ 23.63万 - 项目类别:
GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
- 批准号:
10577811 - 财政年份:2021
- 资助金额:
$ 23.63万 - 项目类别:
GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
- 批准号:
10162829 - 财政年份:2021
- 资助金额:
$ 23.63万 - 项目类别:
GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens
GmPcides:解除多种革兰氏阳性病原体抗生素耐药性的化合物
- 批准号:
10352471 - 财政年份:2021
- 资助金额:
$ 23.63万 - 项目类别:
Structure-function analysis of type IVB secretion systems
IVB型分泌系统的结构-功能分析
- 批准号:
10624264 - 财政年份:2019
- 资助金额:
$ 23.63万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
9304949 - 财政年份:2014
- 资助金额:
$ 23.63万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
8759401 - 财政年份:2014
- 资助金额:
$ 23.63万 - 项目类别:
EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI
粪肠球菌中 EBPA-纤维原的相互作用
- 批准号:
8901925 - 财政年份:2014
- 资助金额:
$ 23.63万 - 项目类别:
CATABOLITE REPRESSION CONTROLS VIRULENCE IN STREPTOCOCCUS PYOGENES
分解代谢物抑制控制化脓性链球菌的毒力
- 批准号:
9174072 - 财政年份:2007
- 资助金额:
$ 23.63万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 23.63万 - 项目类别:
Research Grant