Determination of the Interactome between Haemophilus ducreyi and the Human Host.
Determination of the Interactome between Haemophilus ducreyi and the Human Host.
批准号:
10531548
负责人:
Stanley M. Spinola
金额:
$58.04万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-12-17 至 2024-11-30
关键词:
AbscessAdultAffectAfricaAnaerobiosisAnnual ReportsAntibioticsAscorbic AcidAsiaAzithromycinBacteriaBacterial GenesBacterial InfectionsBindingBiologyCarbonCase StudyCellsChancroidsChildChronicCommunicable DiseasesCountryCutaneousDataDevelopmentDiseaseEndemic DiseasesGene ExpressionGenesGenetic TranscriptionGenitalGenitaliaGrowthHIVHIV-1Hemophilus ducreyiHost DefenseHumanHuman VolunteersImmune responseIn VitroIndividualInfectionInfectious Skin DiseasesIonsLeprosyLesionMacrophageMetabolicMetalsMicro Array DataModelingMolecularMusNutrientNutritionalOrganismPapua New GuineaPathogenesisPathway interactionsPhagocytesPhagocytosisPharmaceutical PreparationsPublicationsSiteSkinSkin colonizationSourceTestingTissuesTranscriptTreponema pallidumUlcerUpper armVaccinesVirulenceWorld Health OrganizationYawscase findingdisabilityextracellularflygenome sequencingin vivoinfection riskinsightmetabolomemetabolomicsneglected tropical diseasesneutrophilnovel strategiespathogenpressureresponsesingle-cell RNA sequencingskin disordertherapeutic developmenttranscriptome sequencingtransmission processuptakevolunteerwhole genome
中文摘要
在我们对传染病的理解中,一个主要的空白是缺乏分子间相互作用的信息
感染病原体和人类宿主之间的网络,这对于细菌来说还没有完成。
人类感染。本申请的目的是在转录水平上定义相互作用基因组,
使用RNA在实验感染的人类志愿者中的主要皮肤病原体杜克雷嗜血杆菌(HD)
测序(RNA-seq)和代谢组学。HD导致软下疳,这是一种生殖器溃疡(GU)疾病,
艾滋病毒的传播,是一个主要的原因皮肤溃疡(CU)的儿童在雅司病流行的国家。
用抗生素根除HD相关CU的努力由于环境水库而失败。研究
HD生物学,我们开发了一个模型,其中HD GU菌株35000 HP及其衍生物接种
植入成年志愿者上臂的皮肤中。全基因组测序显示,大多数CU菌株是
与35000 HP几乎相同,表明我们的模型与GU和CU高度相关。在模型中,
天然软下疳,HD存在于脓肿中,周围被多形核白细胞包围,
通过逃避吞噬作用而保持在细胞外。在我们新的初步数据中,我们显示
HD和宿主之间存在相互作用网络,宿主和细菌的差异转录物
表达与感染部位相对于受伤部位的代谢组学变化相关。HD主要上调
参与适应厌氧生活和吸收利用金属离子的基因的表达,
替代碳源,如抗坏血酸,符合“营养毒性”的想法。我们的新
代谢组学数据显示抗坏血酸途径在损伤中上调。因此,我们假设,
宿主调节其基因转录以吞噬和限制营养物到HD,HD调节其
基因转录来抵消这些宿主防御,宿主基因表达与
在感染部位的代谢谱,以及细菌基因参与适应
由宿主反应产生的代谢生态位将是毒力所必需的。我们的具体目标是:(1)
定义代谢组和感染组织中HD与人类宿主之间的相互作用组,
将宿主转录反应与病变中的代谢变化相关联; 2)鉴定负责的细胞
使用单细胞RNA-seq进行宿主转录反应; 3)确定HD基因是否
参与利用宿主生态位的基因是人类毒力所必需的,
这些基因有助于毒性。这项研究的重要性在于,我们将首先确定一个
在细菌人类感染位点的相互作用体,定义了负责转录的宿主细胞。
反应,将宿主反应与病变中的代谢组学变化相关联,并研究HD如何利用这些变化。
代谢物。我们将提供新的见解之间的相互作用模型细胞外细菌和
揭示了控制HD相关CU新策略。
英文摘要
A major gap in our understanding of infectious diseases is the lack of information about molecular interaction
networks between an infecting pathogen and the human host, which has yet to be accomplished for a bacterial
infection in humans. The purpose of this application is to define an interactome on a transcript level for the
primary skin pathogen, Haemophilus ducreyi (HD), in experimentally infected human volunteers using RNA
sequencing (RNA-seq) and metabolomics. HD causes chancroid, a genital ulcer (GU) disease that facilitates
HIV transmission and is as a major cause of cutaneous ulcers (CU) in children in yaws-endemic countries.
Efforts to eradicate HD-associated CU with antibiotics failed due to environmental reservoirs. To study the
biology of HD, we developed a model in which the HD GU strain 35000HP and its derivatives are inoculated
into the skin of the upper arm of adult volunteers. Whole genome sequencing shows that most CU strains are
nearly identical to 35000HP, indicating that our model is highly relevant to GU and CU. In the model and in
natural chancroid, HD resides in an abscess where it is surrounded by polymorphonuclear leukocytes and
macrophages and remains extracellular by evading phagocytosis. In our new preliminary data, we show
that an interaction network exists between HD and the host and that differential host and bacterial transcript
expression correlates with metabolomic changes at infected vs. wounded sites. HD primarily upregulates the
expression of genes involved in adapting to anaerobiosis and uptake and utilization of metal ions and
alternative carbon sources, such as ascorbic acid, consistent with the idea of “nutritional virulence.” Our new
metabolomics data show that ascorbic acid pathways are upregulated in lesions. Thus, we hypothesize that
the host regulates its gene transcription to phagocytize and limit nutrients to HD, that HD regulates its
gene transcription to counteract these host defenses, that host gene expression correlates with
metabolomic profiles at infected sites, and that bacterial genes that are involved in adaptation to the
metabolic niche created by the host response will be required for virulence. Our specific aims are 1) to
define the metabolome and the interactome between HD and the human host in infected tissue and to
correlate the host transcriptional response to metabolic changes in lesions; 2) to identify the cells responsible
for the host transcriptional response using single cell RNA-seq; 3) to determine whether the HD genes
involved in exploitation of the host niche are required for virulence in humans and the mechanism(s) by which
these genes contribute to virulence. The importance of this study is that we will be the first to determine an
interactome at a site of a bacterial human infection, define the host cells responsible for the transcriptional
response, correlate the host response to metabolomic changes in lesions, and study how HD exploits these
metabolites. We will provide new insights into the interaction between a model extracellular bacterium and the
human host and unmask novel strategies to control HD-associated CU.
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会议论文
Determination of the Interactome between Haemophilus ducreyi and the Human Host.
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批准号:9885152
-
项目类别:
-
资助金额:$65.24万
-
财政年份:2019
-
负责人:Stanley M. Spinola
-
依托单位:
Determination of the Interactome between Haemophilus ducreyi and the Human Host.
-
批准号:10305633
-
项目类别:
-
资助金额:$62.25万
-
财政年份:2019
-
负责人:Stanley M. Spinola
-
依托单位:
Pathogenesis of Haemophilus Ducreyi Infections
-
批准号:8238075
-
项目类别:
-
资助金额:$11.34万
-
财政年份:2012
-
负责人:Stanley M. Spinola
-
依托单位:
Biennial Symposium of H. ducreyi Pathogenesis and Chancroid
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批准号:8130005
-
项目类别:
-
资助金额:$0.8万
-
财政年份:2011
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负责人:Stanley M. Spinola
-
依托单位:
Administrative Core
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批准号:7962288
-
项目类别:
-
资助金额:$7.08万
-
财政年份:2008
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负责人:Stanley M. Spinola
-
依托单位:
Chancroid Human Challenge Unit (CHCU)
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批准号:7962282
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项目类别:
-
资助金额:$18.28万
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财政年份:2008
-
负责人:Stanley M. Spinola
-
依托单位:
Human Immune Response to Haemophilus Ducreyi Infection
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批准号:7336755
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项目类别:
-
资助金额:$36.98万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
Human Immune Response to Haemophilus Ducreyi Infection
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批准号:7752614
-
项目类别:
-
资助金额:$35.94万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
Human Immune Response to Haemophilus Ducreyi Infection
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批准号:8009845
-
项目类别:
-
资助金额:$35.55万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
Human Immune Response to Haemophilus Ducreyi Infection
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批准号:7534041
-
项目类别:
-
资助金额:$36.32万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
EVALUATION OF AN WECA MUTANT IN EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS
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批准号:7717569
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项目类别:
-
资助金额:$0.01万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
Human Immune Response to Haemophilus Ducreyi Infection
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批准号:7195302
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项目类别:
-
资助金额:$38.74万
-
财政年份:2007
-
负责人:Stanley M. Spinola
-
依托单位:
EVALUATION OF AN WECA MUTANT IN EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS
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批准号:7606472
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项目类别:
-
资助金额:$0.12万
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财政年份:2006
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负责人:Stanley M. Spinola
-
依托单位:
EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS DUCREYI
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批准号:7606366
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项目类别:
-
资助金额:$0.27万
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财政年份:2006
-
负责人:Stanley M. Spinola
-
依托单位:
EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS DUCREYI IN PERSONS WHO ARE HIV
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批准号:7379081
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项目类别:
-
资助金额:$0.29万
-
财政年份:2005
-
负责人:Stanley M. Spinola
-
依托单位:
EVALUATION OF AN DLTA MUTANT IN EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS
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批准号:7379137
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项目类别:
-
资助金额:$1.11万
-
财政年份:2005
-
负责人:Stanley M. Spinola
-
依托单位:
Biennial Symposium on H.ducreyi Pathogenesis & Chancroid
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批准号:7255443
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项目类别:
-
资助金额:$0.6万
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财政年份:2005
-
负责人:Stanley M. Spinola
-
依托单位:
EXPERIMENTAL HUMAN INFECTION WITH HAEMOPHILUS DECREYI
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批准号:7205737
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项目类别:
-
资助金额:$1.92万
-
财政年份:2005
-
负责人:Stanley M. Spinola
-
依托单位:
Biennial Symposium on H.ducreyi Pathogenesis and Chancroid
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批准号:7640600
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项目类别:
-
资助金额:$0.6万
-
财政年份:2005
-
负责人:Stanley M. Spinola
-
依托单位:
EVALUATION OF AN OMPP2A OMPP2B DOUBLE MUTANT IN EXPERIMENTAL HUMAN INFECTION
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批准号:7379133
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项目类别:
-
资助金额:$0.48万
-
财政年份:2005
-
负责人:Stanley M. Spinola
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依托单位:
海外基金