Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses
确定宿主因素对金黄色葡萄球菌脓肿分子结构和细菌生理学的影响
基本信息
- 批准号:10115595
- 负责人:
- 金额:$ 75.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAbscessAddressAnimalsAnti-Bacterial AgentsAppearanceArchitectureAttentionBacteriaBacterial InfectionsBacterial PhysiologyBacterial ProteinsBindingBiologyCellsCharacteristicsComplexCuesDataDetectionDevelopmentDiabetes MellitusDiseaseEffector CellEvolutionFluorescence MicroscopyFluorescent in Situ HybridizationGenus staphylococcusHeterogeneityHistologicHistologyHyperglycemiaImageImaging DeviceImmuneImmune responseImmunohistochemistryIn SituIndividualInfectionInflammatoryInnate Immune ResponseIntegration Host FactorsKnowledgeLesionLinkMaintenanceMass Spectrum AnalysisMedicalMethodsMicrobeModelingMolecularMurine Tissue TypeMyelosuppressionOrganOsteomyelitisOutcomePathogenesisPathologyPatientsPeptidesPhysiologyPopulationPredispositionProteomicsPublishingReagentRoleShapesSpace PerceptionSpatial DistributionStaphylococcal InfectionsStaphylococcus aureusStaphylococcus aureus infectionTechniquesTestingTherapeuticTherapeutic InterventionTimeTissue SampleTissue imagingTissuesTranslational ResearchVaccinesWorkantimicrobialbasebody systemcell typecomorbidityexperimental studyhuman pathogenimaging platformin vivoinnovationlaser capture microdissectionmacrophagemicrobialmicrobial hostmolecular imagingmouse modelneutrophilnovelnovel therapeuticspathogenpreservationresponsetherapeutic candidatetissue processingtranscriptome sequencingtranslational medicine
项目摘要
PROJECT SUMMARY / ABSTRACT
Staphylococcus aureus is capable of infecting nearly every vertebrate organ system, triggering the formation
of characteristic tissue lesions known as abscesses. Understanding how S. aureus survives within abscesses is
critical to the development of new therapeutics, as these lesions represent the pathogen niche during infection.
In this application, we will leverage a powerful mass spectrometry-based imaging platform to identify host and
bacterial factors that contribute to staphylococcal disease. By defining how tissue niche and host biology drive
molecular heterogeneity in abscesses, we will uncover new targets for tailored anti-staphylococcal therapeutics.
Historically, it has been technically challenging to study the bacterial and host factors that contribute to
abscess physiology for two primary reasons. First, approaches that seek to preserve abscess architecture within
a tissue sample are inherently limited to the study of known microbial and host targets. This applies to techniques
such as immunohistochemistry and fluorescence in situ hybridization, which can define the spatial distribution of
analytes in a tissue but rely on pre-existing knowledge of targets. These approaches, by definition, cannot be
used to discover unknown bacterial or host factors that contribute to disease. Conversely, discovery-based
methods such as RNA sequencing or proteomics can identify novel, disease-associated analytes, but require
destructive tissue processing that eliminates information regarding the spatial orientation of microbial and host
molecules. To overcome these technical limitations, we created a mass spectrometry-based imaging platform to
identify host and microbial analytes in abscessed tissue during invasive S. aureus infection. Because imaging
mass spectrometry (IMS) does not require probes or detection reagents, this platform can define the localization
and abundance of abscess-associated analytes in a spatially-defined manner, thereby enabling the discovery of
microbial and host factors that contribute to disease pathogenesis. When applied to a model of disseminated S.
aureus infection, this IMS-based platform enabled three-dimensional molecular imaging of the staphylococcal-
host interface and powered the discovery of bacterial proteins that mark the pathogen niche within abscesses.
Although individual abscesses typically have a similar histologic appearance, our IMS-based analysis
revealed significant molecular heterogeneity between S. aureus lesions. We hypothesize that abscesses display
molecular heterogeneity in response to tissue niche, antibacterial immune responses, and comorbid host
conditions. To test this hypothesis, we will couple our IMS platform with laser capture microdissection to enable
spatially-resolved proteomics of the staphylococcal-host interface. The proposed Aims will define the molecular
architecture of abscesses across S. aureus infected tissues and determine how innate immune effector cells and
host comorbidities drive heterogeneity in bacterial physiology and abscess molecular architecture in situ. In total,
these experiments will decipher how host biology drives molecular heterogeneity during invasive infection.
项目总结/摘要
金黄色葡萄球菌能够感染几乎所有脊椎动物的器官系统,从而引发病毒的形成
一种称为“脓肿”的特征性组织损伤了解S。金黄色葡萄球菌生存在阴道内,
这对新疗法的开发至关重要,因为这些病变代表了感染期间的病原体生态位。
在这个应用中,我们将利用一个强大的基于质谱的成像平台来识别宿主,
导致葡萄球菌病的细菌因素。通过定义组织生态位和宿主生物学如何驱动
分子异质性,我们将发现新的目标,定制的抗葡萄球菌治疗。
从历史上看,研究细菌和宿主因素导致的疾病在技术上一直具有挑战性。
脓肿生理学有两个主要原因。首先,寻求保留脓肿结构的方法
组织样品固有地局限于研究已知的微生物和宿主靶标。这适用于技术
如免疫组织化学和荧光原位杂交,它们可以确定
组织中的分析物,但依赖于预先存在的目标知识。从定义上讲,这些方法不能
用于发现未知的细菌或导致疾病的宿主因素。相反,基于发现的
RNA测序或蛋白质组学等方法可以鉴定新的疾病相关分析物,但需要
破坏性的组织处理,其消除关于微生物和宿主的空间取向的信息
分子。为了克服这些技术限制,我们创建了一个基于质谱的成像平台,
在侵入性S.金黄色葡萄球菌感染。因为成像
质谱(IMS)不需要探针或检测试剂,该平台可以定义定位
以及以空间限定的方式富集与生物学相关的分析物,从而能够发现
微生物和宿主因素,有助于疾病的发病机制。当应用到一个模型的传播S。
金黄色葡萄球菌感染,这个基于IMS的平台使三维分子成像的葡萄球菌,
宿主界面,并推动了细菌蛋白质的发现,标志着病原体生态位内的细菌。
虽然个体乳腺癌通常具有相似的组织学表现,但我们基于IMS的分析表明,
揭示了S.金黄色病变。我们假设,
对组织生态位、抗菌免疫反应和共病宿主反应的分子异质性
条件为了验证这一假设,我们将IMS平台与激光捕获显微切割相结合,
葡萄球菌-宿主界面的空间分辨蛋白质组学。拟议的目标将定义分子
跨S.金黄色葡萄球菌感染的组织,并确定如何先天免疫效应细胞和
宿主共病导致细菌生理学和原位脓肿分子结构的异质性。总的来说,
这些实验将解释宿主生物学如何在侵入性感染期间驱动分子异质性。
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 }}
JAMES E CASSAT其他文献
JAMES E CASSAT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('JAMES E CASSAT', 18)}}的其他基金
Mechanisms of antibiotic failure during osteomyelitis
骨髓炎期间抗生素失效的机制
- 批准号:
10737292 - 财政年份:2023
- 资助金额:
$ 75.55万 - 项目类别:
Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis
金黄色葡萄球菌骨髓炎发病机制中的差异炎症小体调节
- 批准号:
10388546 - 财政年份:2021
- 资助金额:
$ 75.55万 - 项目类别:
Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis
金黄色葡萄球菌骨髓炎发病机制中的差异炎症小体调节
- 批准号:
10677704 - 财政年份:2021
- 资助金额:
$ 75.55万 - 项目类别:
Differential Inflammasome Regulation in the pathogenesis of S. aureus osteomyelitis
金黄色葡萄球菌骨髓炎发病机制中的差异炎症小体调节
- 批准号:
10493396 - 财政年份:2021
- 资助金额:
$ 75.55万 - 项目类别:
Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses
确定宿主因素对金黄色葡萄球菌脓肿分子结构和细菌生理学的影响
- 批准号:
9973597 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses
确定宿主因素对金黄色葡萄球菌脓肿分子结构和细菌生理学的影响
- 批准号:
10356907 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses
确定宿主因素对金黄色葡萄球菌脓肿分子结构和细菌生理学的影响
- 批准号:
10565912 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
The impact of hypoxia on Staphylococcus aureus metabolism and virulence during osteomyelitis
骨髓炎期间缺氧对金黄色葡萄球菌代谢和毒力的影响
- 批准号:
9901431 - 财政年份:2017
- 资助金额:
$ 75.55万 - 项目类别:
Host-pathogen interactions during osteomyelitis
骨髓炎期间宿主与病原体的相互作用
- 批准号:
9273893 - 财政年份:2014
- 资助金额:
$ 75.55万 - 项目类别:
相似海外基金
Maturation and resolution of Staphylococcus aureus skin abscess
金黄色葡萄球菌皮肤脓肿的成熟和消退
- 批准号:
MR/Y000447/1 - 财政年份:2024
- 资助金额:
$ 75.55万 - 项目类别:
Fellowship
S. aureus virulence factor expression during kidney abscess formation
肾脓肿形成过程中金黄色葡萄球菌毒力因子的表达
- 批准号:
10610817 - 财政年份:2022
- 资助金额:
$ 75.55万 - 项目类别:
S. aureus virulence factor expression during kidney abscess formation
肾脓肿形成过程中金黄色葡萄球菌毒力因子的表达
- 批准号:
10370868 - 财政年份:2022
- 资助金额:
$ 75.55万 - 项目类别:
Characterization of T7SS in S. intermedius isolated from brain abscess to blood-brain barrier disruption
从脑脓肿分离到血脑屏障破坏的中间链球菌中 T7SS 的特征
- 批准号:
20K16257 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Optical property measurement in human abscess cavities for photodynamic therapy treatment planning
人体脓肿腔光学特性测量,用于光动力疗法治疗计划
- 批准号:
10385790 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Optical property measurement in human abscess cavities for photodynamic therapy treatment planning
人体脓肿腔光学特性测量,用于光动力疗法治疗计划
- 批准号:
10025874 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Optical property measurement in human abscess cavities for photodynamic therapy treatment planning
人体脓肿腔光学特性测量,用于光动力疗法治疗计划
- 批准号:
10190942 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Combinational therapy with antibiotics and antibiotic-loaded adipose-derived stem cells reduce abscess formation in implant-related infection in rats
抗生素和负载抗生素的脂肪干细胞联合治疗可减少大鼠植入相关感染中脓肿的形成
- 批准号:
20K18057 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Optical property measurement in human abscess cavities for photodynamic therapy treatment planning
人体脓肿腔光学特性测量,用于光动力疗法治疗计划
- 批准号:
10611934 - 财政年份:2020
- 资助金额:
$ 75.55万 - 项目类别:
Exploratory research for new methodology of diagnosis and treatments of gynecological pelvic abscess using MR Spectroscopy and Identification of bacteria species by NGS.
使用磁共振波谱和NGS鉴定细菌种类的妇科盆腔脓肿诊断和治疗新方法的探索性研究。
- 批准号:
18K16779 - 财政年份:2018
- 资助金额:
$ 75.55万 - 项目类别:
Grant-in-Aid for Early-Career Scientists