MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
基本信息
- 批准号:10539270
- 负责人:
- 金额:$ 41.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:16S ribosomal RNA sequencingAcetatesAddressAntibiotic TherapyBacteriaBinding ProteinsBiological AvailabilityBrazilCell Surface ReceptorsCessation of lifeChemotactic FactorsClostridium difficileColectomyCollaborationsDataDiarrheaEpithelial CellsFFAR2 geneGene Expression ProfileGenetic TranscriptionGerm-FreeGoalsGrowthHealthHospitalizationHost DefenseHumanImmune responseIn VitroIncidenceInfectionInfection preventionInflammasomeInterleukin-1 betaIntestinesJointsLaboratoriesLymphoidLymphoid CellMediatingMetabolismMucosal Immune ResponsesMucous MembraneMusNatural ImmunityNeutrophil ActivationNeutrophil InfiltrationOrganogenesisPatientsPlayProductionProductivityProtein DeficiencyPseudomembranous ColitisRecurrenceRegulationResistanceRoleSecureSeveritiesSignal TransductionSurfaceTestingTherapeuticTherapeutic InterventionTimeToxic MegacolonToxinTranslatingTreatment FailureVolatile Fatty AcidsWorkantimicrobialantimicrobial peptidecell typecohortdysbiosisexperimental studyfecal transplantationforgingfundamental researchgut microbiotahigh riskin vivoinnovationinterleukin-22intestinal epitheliummetabolomicsmicrobialmicrobiotamortalityneutrophilnovelprotective effectreceptorresponsesynergismtranscriptometranslational potential
项目摘要
PROJECT SUMMARY
The overall goal of this application is to establish avenues through which we can harness the intestinal microbiota
to enhance mucosal immune responses against Clostridium difficile. C. difficile infection (CDI) is a common
cause of diarrhea in hospitalized patients and represents a major health threat due to frequent treatment failures
and high risks of colectomy and mortality. Patients with recurrent CDI do not benefit from conventional
antimicrobial therapies; while transplantation of fecal microbiota derived from healthy donors might be a valid
option, regulation of fecal transplantation is problematic. In our preliminary data we show for the first time a
remarkable impact of microbiota-derived acetate on CDI, which may constitute a potential therapeutic avenue.
We show that acetate enhances neutrophil and innate lymphoid cells of type 3 (ILC3) responses through the
surface receptor FFAR2. Moreover, we show that lack of a decoy receptor for IL-22, known as IL-22 binding
protein (IL-22BP), amplifies the activity of IL-22 and modifies the microbiota, strengthening its resistance to CDI.
We propose three specific aims. In Specific Aim 1, we will test the mechanisms through which acetate-FFAR2
signaling activates the neutrophil response to CDI. We will perform in vitro functional and transcriptional
experiments to determine whether FFAR2 promotes neutrophil recruitment to chemoattractants, upregulates
expression of inflammasome components, alters the neutrophil transcriptional profile, and/or modifies neutrophil
metabolism. The impact of acetate on human neutrophils will be examined as well. In Specific Aim 2, using newly
generated mice lacking FFAR2 in ILC3s, along with mice lacking FFAR2 in neutrophils, we will determine
whether FFAR2 mediated activation of ILC3s is necessary and sufficient to recapitulate the protective effect of
acetate in vivo. Furthermore, we will determine whether FFAR2 impacts ILC3-mediated lymphoid organogenesis
in the steady state and whether FFAR2 modifies the transcriptome and/or metabolism of mouse and human
ILC3s. Finally, we will ascertain whether acetate can be used in a therapeutic mode. In Specific Aim 3, we will
test the hypothesis that lack of IL-22BP and the resulting increased basal activity of IL-22 modify the intestinal
microbiota in a manner that facilitates the colonization of bacterial cohorts that enhance protection against CDI.
This work is significant because it addresses the major health burden of dysbiosis and CDI, is innovative because
it evaluates alternative therapeutic approaches based on acetate and/or blockade of IL-22BP rather than live
microbiota and has potential to translate into novel treatments with implications for health and productivity. The
project will be accomplished through the ongoing collaboration between the Colonna lab in USA and the Vinolo
lab in Brazil, each with distinct and complementary sets of expertise on CDI, short chain fatty acids, and mucosal
innate immunity that must be combined to successfully complete this project. The synergy between the two labs
has already generated results that serve as the basis for this proposal and will produce fundamental research
on the impact of the microbiota on mucosal responses to CDI and unveil new potential therapies.
项目总结
这个应用程序的总体目标是建立我们可以利用肠道微生物区系的途径
增强对艰难梭菌的黏膜免疫应答。艰难梭菌感染(CDI)是一种常见的
是住院患者腹泻的原因,由于频繁的治疗失败,是一个主要的健康威胁
以及结肠切除和死亡率的高风险。复发的CDI患者不能从传统的
抗菌治疗;而来自健康捐赠者的粪便微生物群移植可能是一种有效的
作为一种选择,对粪便移植的监管是有问题的。在我们的初步数据中,我们第一次显示了
微生物区系衍生的醋酸盐对CDI的影响显著,这可能是一种潜在的治疗途径。
我们发现,醋酸盐通过增强中性粒细胞和3型固有淋巴样细胞(ILC3)的反应
表面受体FFAR2。此外,我们发现缺乏IL-22的诱饵受体,称为IL-22结合
蛋白(IL-22BP),放大IL-22的活性,改变微生物区系,增强其对CDI的抵抗力。
我们提出了三个具体目标。在特定的目标1中,我们将测试乙酸盐-FFAR2通过的机制
信号转导激活中性粒细胞对CDI的反应。我们将在体外进行功能和转录
确定FFAR2是否促进中性粒细胞对趋化物质募集的实验,上调
炎症体成分的表达,改变中性粒细胞的转录图谱,和/或改变中性粒细胞
新陈代谢。此外,还将研究醋酸盐对人类中性粒细胞的影响。在具体目标2中,使用新的
产生的ILC3中缺乏FFAR2的小鼠,以及中性粒细胞中缺乏FFAR2的小鼠,我们将确定
FFAR2介导的ILC3的激活是否必要且充分地概括了
体内的醋酸盐。此外,我们将确定FFAR2是否影响ILC3介导的淋巴器官发生
在稳态以及FFAR2是否改变小鼠和人的转录组和/或代谢
ILC3s。最后,我们将确定醋酸盐是否可以用于治疗模式。在具体目标3中,我们将
验证缺乏IL-22BP和由此导致的IL-22基础活性增加改变肠道的假设
微生物区系,以促进细菌群的定居,从而加强对CDI的保护。
这项工作意义重大,因为它解决了生物失调和CDI的主要健康负担,具有创新性,因为
它评估了基于醋酸盐和/或阻断IL-22BP而不是LIVE的替代治疗方法
微生物区系,并有可能转化为对健康和生产力有影响的新治疗方法。这个
该项目将通过美国Colonna实验室和Vinolo之间的持续合作完成
在巴西的实验室,每个实验室在CDI、短链脂肪酸和粘膜方面都有不同和互补的专业知识
必须结合先天免疫力才能成功完成这个项目。两个实验室之间的协同作用
已经产生了作为这项提议的基础的结果,并将产生基础研究
关于微生物区系对CDI黏膜反应的影响,并推出新的潜在治疗方法。
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)
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MARCO COLONNA其他文献
MARCO COLONNA的其他文献
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{{ truncateString('MARCO COLONNA', 18)}}的其他基金
Mucosal Immune Defense Mechanisms of the Urinary Bladder
膀胱粘膜免疫防御机制
- 批准号:
10587639 - 财政年份:2023
- 资助金额:
$ 41.03万 - 项目类别:
Soluble TREM2 regulation of microglial function in Alzheimer disease
可溶性 TREM2 对阿尔茨海默病小胶质细胞功能的调节
- 批准号:
10432584 - 财政年份:2022
- 资助金额:
$ 41.03万 - 项目类别:
Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis
多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响
- 批准号:
10528082 - 财政年份:2022
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$ 41.03万 - 项目类别:
The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease
蛋白质酪氨酸激酶 SYK 驱动针对阿尔茨海默病的先天免疫反应
- 批准号:
10674689 - 财政年份:2022
- 资助金额:
$ 41.03万 - 项目类别:
Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis
多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响
- 批准号:
10623342 - 财政年份:2022
- 资助金额:
$ 41.03万 - 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
- 批准号:
10446266 - 财政年份:2022
- 资助金额:
$ 41.03万 - 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
- 批准号:
10557870 - 财政年份:2022
- 资助金额:
$ 41.03万 - 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
- 批准号:
10477296 - 财政年份:2021
- 资助金额:
$ 41.03万 - 项目类别:
MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
- 批准号:
10321553 - 财政年份:2021
- 资助金额:
$ 41.03万 - 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
- 批准号:
10279674 - 财政年份:2021
- 资助金额:
$ 41.03万 - 项目类别:
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