Host-derived biomarker signatures for the diagnosis of acute rickettsial diseases
用于诊断急性立克次体病的宿主衍生生物标志物特征
基本信息
- 批准号:10427237
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:Accident and Emergency departmentAcuteAcute DiseaseAffectAntibody titer measurementBacterial InfectionsBiologicalBiological AssayBlood specimenClinicalComplexDataData SetDecision MakingDengue FeverDevelopmentDiagnosisDiagnosticDiseaseEnrollmentFeverFoundationsFunctional disorderGene ExpressionGene Expression ProfileGenesGenomicsGeographyHealthHospitalizationHumanImmune responseIndividualInfectionInflammatoryInfrastructureInternationalLaboratoriesLeukocytesLiteratureMedical centerMethodologyModalityModelingOrganismPathway interactionsPatientsPopulations at RiskProcessPublishingRespiratory Tract InfectionsReverse Transcriptase Polymerase Chain ReactionRickettsiaRickettsia InfectionsRickettsia rickettsiiRocky Mountain Spotted FeverSamplingScrub TyphusSensitivity and SpecificitySerology testStatistical ModelsSystemTestingTherapeuticTimeTranslatingUnited StatesUnited States Department of Veterans AffairsVector-transmitted infectious diseaseVeteransViralVirus DiseasesWhole BloodWorkZoonosesaccurate diagnosisactive dutyarboviral diseasebiobankbiomarker signatureclinically relevantcohortcomplex datacross reactivitydesigndetection platformdiagnostic assaydiagnostic valuedisease diagnosiseffective therapyexpectationexperimental studygenetic signaturegenomic signaturehigh dimensionalitymembermigrationmortalitynovelparticipant enrollmentpathogenperipheral bloodpoint of carepractical applicationservice memberspotted feversuccesstranscriptome sequencingvector-bornewarfighter
项目摘要
Rickettsial diseases such as those caused by Spotted Fever Group rickettsii (SFGR) and Scrub typhus
(ST) are estimated to account for millions of illnesses a year worldwide. SFGR infections affect Veterans and
other members of the public throughout the US, and both SFGR and Scrub typhus are continuous threats to
active duty warfighters stationed throughout the world. Effective therapy exists, but there is currently no clinically
available test capable of yielding reliable diagnostic information within the timeframe required to guide
therapeutic decisions. Through this proposal we intend to explore the pathophysiology of natural human infection
with SFGR and ST as defined by the host response, and to utilize this information to generate a practical test
capable of diagnosing these diseases in the acute setting. Prior published work and our preliminary data suggest
that these rickettsial infections trigger conserved inflammatory pathways in human hosts, and it is these unique
host responses that we will harness in order to identify patterns of gene expression within circulating white blood
cells that identify the presence of these organisms in febrile patients. In order to generate such a ‘signature’ of
infection, this project will utilize a unique combination of two main clinical cohorts. The first cohort is made up of
US Veterans with acute rickettsial illness diagnosed here in the US, both previously enrolled patients with acute
SFGR infection as well as ongoing enrollment of new cases. The second cohort is made up of a large existing
sample set of individuals enrolled from around the world with a variety of acute febrile SFGR infections as well
as Scrub typhus, which we have shown mimics the host responses seen in SFGR infection. This combination
will give us the ability to generate a rickettsial gene signature that both identifies acute disease in Veterans here
in the US as well as having the potential for utility beyond our borders for travelers and active duty military
members stationed internationally. We will utilize RNA Sequencing (RNASeq) to identify complex patterns of
gene expression in peripheral blood samples from subjects and controls with other types of febrile illnesses
(including viral and bacterial infections, both from the US and globally). However, high dimensional RNASeq
analysis is not a modality that can produce diagnostic answers in a clinically relevant timeframe. Therefore, we
will ‘prune’ these complex signature(s) down to smaller genomic classifiers appropriate for RT-PCR platforms,
as using RT-PCR probes lends itself to both existing clinical laboratory infrastructure as well as to a number of
burgeoning point-of-care platforms in development, thus beginning the final steps towards bringing such a test
to the point of actual clinical utility. Thus, through this proposal we intend to explore the pathophysiology of
natural human infection with SFGR and Scrub typhus as defined by the host response, and to utilize this
information to build systems-based models with diagnostic capability. It is therefore our expectation that not only
will these experiments provide us with exciting new data about a largely unexplored aspect of the host response
to infections with true global impact, but that they will lay the foundation for translating these findings into practical
applications with a direct impact on public and Veteran health.
立克次体疾病,如斑点热群立克次体(SFGR)和恙虫病引起的疾病
(ST)据估计,全球每年有数百万人因此患病。SFGR感染影响退伍军人和
其他成员的公众在整个美国,和SFGR和丛林斑疹伤寒都是持续的威胁,
驻扎在世界各地的现役战士。有效的治疗是存在的,但目前没有临床上
能够在指导所需的时间范围内产生可靠诊断信息的可用测试
治疗决定。通过这一建议,我们打算探索自然人类感染的病理生理学
与主机响应定义的SFGR和ST,并利用此信息生成实际测试
能够在急性情况下诊断这些疾病先前发表的工作和我们的初步数据表明,
这些立克次体感染触发了人类宿主中保守的炎症途径,正是这些独特的
我们将利用这些宿主反应来鉴定循环白色血液中的基因表达模式
在发热患者中识别这些微生物存在的细胞。为了生成这样的“签名”,
感染,该项目将利用两个主要临床队列的独特组合。第一组是由
美国退伍军人与急性立克次体病诊断在这里在美国,都以前招募患者急性
SFGR感染以及正在招募的新病例。第二组由现有的大型
从世界各地招募的患有各种急性发热性SFGR感染的个体样本集
与恙虫病一样,我们已经证明它模仿了SFGR感染中的宿主反应。这种组合
将使我们有能力产生立克次体基因签名,
在美国,以及有潜力的效用超越我们的边界,为旅客和现役军人
派驻国际的成员。我们将利用RNA测序(RNASeq)来识别复杂的模式,
来自患有其他类型发热性疾病的受试者和对照者的外周血样品中的基因表达
(包括来自美国和全球的病毒和细菌感染)。然而,高维RNASeq
分析不是能够在临床相关时间范围内产生诊断答案的模态。所以我们
将“修剪”这些复杂的签名,使其成为适合于RT-PCR平台的更小的基因组分类器,
因为使用RT-PCR探针既适用于现有的临床实验室基础设施,
正在开发中的快速护理点平台,从而开始了进行此类测试的最后步骤
达到临床实用的程度。因此,通过这项建议,我们打算探索的病理生理学,
自然人感染SFGR和恙虫病,如宿主反应所定义的,并利用这一点,
信息来构建具有诊断能力的基于系统的模型。因此,我们期望,不仅
这些实验是否会为我们提供有关宿主反应中基本上未探索的方面的令人兴奋的新数据
但他们将为将这些发现转化为实际应用奠定基础。
对公众和退伍军人健康有直接影响的应用。
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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Micah T. McClain其他文献
Single-cell genome-wide association reveals that a nonsynonymous variant in emERAP1/em confers increased susceptibility to influenza virus
- DOI:
10.1016/j.xgen.2022.100207 - 发表时间:
2022-11-09 - 期刊:
- 影响因子:9.000
- 作者:
Benjamin H. Schott;Liuyang Wang;Xinyu Zhu;Alfred T. Harding;Emily R. Ko;Jeffrey S. Bourgeois;Erica J. Washington;Thomas W. Burke;Jack Anderson;Emma Bergstrom;Zoe Gardener;Suzanna Paterson;Richard G. Brennan;Christopher Chiu;Micah T. McClain;Christopher W. Woods;Simon G. Gregory;Nicholas S. Heaton;Dennis C. Ko - 通讯作者:
Dennis C. Ko
Age-associated differences in mucosal and systemic host responses to SARS-CoV-2 infection
与年龄相关的对 SARS-CoV-2 感染的黏膜和全身宿主反应的差异
- DOI:
10.1038/s41467-025-57655-3 - 发表时间:
2025-03-10 - 期刊:
- 影响因子:15.700
- 作者:
Jillian H. Hurst;Aditya A. Mohan;Trisha Dalapati;Ian A. George;Jhoanna N. Aquino;Debra J. Lugo;Trevor S. Pfeiffer;Javier Rodriguez;Alexandre T. Rotta;Nicholas A. Turner;Thomas W. Burke;Micah T. McClain;Ricardo Henao;C. Todd DeMarco;Raul Louzao;Thomas N. Denny;Kyle M. Walsh;Zhaohui Xu;Asuncion Mejias;Octavio Ramilo;Christopher W. Woods;Matthew S. Kelly - 通讯作者:
Matthew S. Kelly
Micah T. McClain的其他文献
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{{ truncateString('Micah T. McClain', 18)}}的其他基金
Host-derived biomarker signatures for the diagnosis of acute rickettsial diseases
用于诊断急性立克次体病的宿主衍生生物标志物特征
- 批准号:
10291785 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Host-derived biomarker signatures for the diagnosis of acute rickettsial diseases
用于诊断急性立克次体病的宿主衍生生物标志物特征
- 批准号:
9860904 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Host-derived biomarker signatures to differentiate acute viral, bacterial, and fungal infection
宿主衍生的生物标志物特征可区分急性病毒、细菌和真菌感染
- 批准号:
9373089 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Genomic signatures for detection of upper respiratory viral infections
用于检测上呼吸道病毒感染的基因组特征
- 批准号:
8333080 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Genomic signatures for detection of upper respiratory viral infections
用于检测上呼吸道病毒感染的基因组特征
- 批准号:
8625188 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Venezuelan Equine Encephalitis Immunology and Vaccine Design
委内瑞拉马脑炎免疫学和疫苗设计
- 批准号:
7642741 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Venezuelan Equine Encephalitis Immunology and Vaccine Design
委内瑞拉马脑炎免疫学和疫苗设计
- 批准号:
7929480 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Venezuelan Equine Encephalitis Immunology and Vaccine Design
委内瑞拉马脑炎免疫学和疫苗设计
- 批准号:
8116627 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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