Human Immune Response to Haemophilus Ducreyi Infection
Human Immune Response to Haemophilus Ducreyi Infection
批准号:
7534041
负责人:
Stanley M. Spinola
金额:
$36.32万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-01-01 至 2011-12-31
关键词:
AbscessBiologyBiopsyBloodCD 200CD44 geneCD58 geneCD80 geneCell CommunicationCell MaturationCellsClinicalCoculture TechniquesDendritic CellsDiseaseEnvironmentEventFailureGenderGene ExpressionGenital systemGermGoalsGranulomaHIVHIV-1Hemophilus ducreyiHistopathologyHomologous GeneHumanHuman GenomeHuman VolunteersIRF1 geneImmuneImmune responseImmunologicsIn VitroInfectionIntercellular adhesion molecule 1Interleukin-10Interleukin-16Interleukin-18Interleukin-7LeadLesionLifeModelingMyelogenousOrganismOutcomePhagocytesPhagocytosisPhenotypePhysiologic pulsePredispositionProliferatingProteomicsPuncture woundResearch PersonnelSerumSimulateSiteSkinStagingT-LymphocyteTLR1 geneTNFRSF5 geneTestingTimeTissue MicroarrayTissuesTranscriptTransudateUlcerUpper armWomanacquired immunityantigen processingbactericidecomparison groupcytokinefallsimmune functionin vitro Modelin vivointerleukin-23killingsmacrophagemenneutrophilnotch proteinpathogenprogramsresponsetransmission process
中文摘要
杜雷伊嗜血杆菌会引起下巴,这会促进艾滋病毒的传播。在一次实验性感染中
在人类的模型中,丘疹在24小时内发育,并溶解或演变为脓疱。脓疱疹含有
由中性粒细胞和巨噬细胞组成的脓肿,而T细胞,髓系树突状细胞(DC)和
巨噬细胞在脓肿下方形成一个疏松的肉芽肿。在失败的脓疱性状态下,H.ducreyi是
被吞噬细胞包围,这些吞噬细胞不吞噬有机体。虽然有些受试者会形成脓疮,但所有
受感染的地方会分解成其他的主题。当脓疮形成者和解决者再次感染时,他们往往
向它们最初的结果分离,确认宿主效应。中性粒细胞和巨噬细胞的分离
两次形成脓疱者(PP组)和两次消退者(RR组)的血液成分无明显差异
吞噬杜氏杆菌的能力,表明感染部位的环境调节吞噬作用。
在第三次感染PP和RR的受试者中,这两组患者的皮损转录本不同,证实了
它们的局部免疫反应是不同的。两组的髓系DC都有共同的转录反应
但每一组都有不同的反应。感染PP DC上调的转录本是
树突状细胞成熟的标记和半成熟或调节性树突状细胞和下调转录的标记
已知可促进DC成熟或抗原处理。感染的RR DC仅上调DC的转录本
成熟。我们的总体假设是,杜氏杆菌与DC的相互作用,以及
感染T细胞的DC是有效(RR)或无效(PP)吞噬反应的关键决定因素
损伤。PP组的DC可能促进调节失调的1型和Tr反应,从而导致
抗吞噬细胞因子环境,而来自RR组的DC促进1型反应,导致
一个有利于吞噬的环境。为了检验这些假设,我们的具体目标包括:比较
RR组和PP组第三次感染后48小时收集的皮损转录本;基因比较
活体白念珠菌暴露后PP组和RR组DC的表达和蛋白质组学特征;
用活的杜氏杆菌冲击DC并与RR组的T细胞共培养是否会导致类型
1反应,而来自PP组的共培养导致1型和Tr反应;检查
杜氏杆菌-DC-T细胞相互作用产生的细胞因子是促进还是抑制巨噬细胞吞噬功能
吞噬作用调节的生物体和机制。我们将在体外确认我们的
结果对再次感染的PP和RR患者的活检进行了观察。
莱昂纳多摘要:杜氏杆菌是一种能引起生殖器溃疡的细菌。当我们感染人类志愿者时
携带着细菌,一些人会患上疾病,而另一些人则会清除感染。我们试图回答一个
重要问题:为什么一些感染了细菌的人会生病,而另一些人则不会?
英文摘要
Haemophilus ducreyi causes chancroid, which facilitates HIV transmission. In an experimental infection
model in humans, papules develop within 24 h and either resolve or evolve into pustules. Pustules contain
an abscess composed of PMNs and macrophages, while T cells, myeloid dendritic cells (DC) and
macrophages form a loose granuloma below the abscess. In the failed pustular state, H. ducreyi is
surrounded by phagocytes that do not ingest the organism. Although pustules form in some subjects, all
infected sites resolve in other subjects. When pustule formers and resolvers are re-infected, they tend to
segregate towards their initial outcome, confirming a host effect. PMNs and macrophages isolated from the
blood of those who formed pustules twice (PP group) or resolved twice (RR group) did not differ in their
ability to ingest H. ducreyi, suggesting that the environment at the site of infection modulates phagocytosis.
In PP and RR subjects infected a third time, lesional transcripts differed between the groups, confriming that
their local immune responses are different. Myeloid DC from both groups had a common transcript response
to H. ducreyi, but each group had unique responses. Infected PP DC upregulated transcripts that were
markers of DC maturation and markers of semi-mature or regulatory DC and downregulated transcripts
known to promote DC maturation or antigen processing. Infected RR DC only upregulated transcripts of DC
maturation. Our overall hypothesis is that the interaction of H. ducreyi with DC, and the interaction of
infected DC with T cells are key determinants of effective (RR) or ineffective (PP) phagocytic responses in
lesions. DC from the PP group likely promote a dysregulated Type 1 and Tr response that leads to an
antiphagocytic cytokine environment, while DC from the RR group promote a Type 1 response that leads to
a pro-phagocytic environment. To test these hypotheses, our specific aims include: comparison of
transcripts in lesions collected 48 h after a third infection of the RR and PP groups; comparison of the gene
expression and proteomic profiles of DC derived from the PP and the RR groups exposed to live H. ducreyi;
testing whether DC pulsed with live H. ducreyi and co-cultured with T cells from the RR group result in Type
1 responses while co-cultures derived from the PP group lead to Type 1 and Tr responses; examination of
whether the cytokines generated by H. ducreyi - DC - T cell interaction promotes or inhibits phagocytosis of
the organism and of the mechanisms underlying the modulation of phagocytosis. We will confirm our in vitro
results with observations made on biopsies obtained from PP and RR subjects who are re-infected.
Lay summary: H. ducreyi is a germ that causes genital ulcers. When we infect human volunteers on the
arm with the germ, some people develop disease while others clear the infection. We seek to answer an
important question: Why do some people who become infected with a germ get sick, while others do not?
期刊论文(0)
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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:10531548
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项目类别:
-
资助金额:$58.04万
-
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:9885152
-
项目类别:
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资助金额:$65.24万
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财政年份:2019
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负责人:Stanley M. Spinola
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依托单位:
Determination of the Interactome between Haemophilus ducreyi and the Human Host.
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批准号:10305633
-
项目类别:
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资助金额:$62.25万
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财政年份:2019
-
负责人:Stanley M. Spinola
-
依托单位:
Pathogenesis of Haemophilus Ducreyi Infections
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批准号:8238075
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项目类别:
-
资助金额:$11.34万
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财政年份:2012
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负责人:Stanley M. Spinola
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依托单位:
Biennial Symposium of H. ducreyi Pathogenesis and Chancroid
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批准号:8130005
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项目类别:
-
资助金额:$0.8万
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财政年份:2011
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负责人:Stanley M. Spinola
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依托单位:
Administrative Core
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批准号:7962288
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项目类别:
-
资助金额:$7.08万
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财政年份:2008
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负责人:Stanley M. Spinola
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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
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项目类别:
-
资助金额:$35.55万
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财政年份:2007
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负责人:Stanley M. Spinola
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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
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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:
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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
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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
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负责人:Stanley M. Spinola
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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
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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
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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
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负责人:Stanley M. Spinola
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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
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财政年份:2005
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负责人:Stanley M. Spinola
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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
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财政年份:2005
-
负责人:Stanley M. Spinola
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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:
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资助金额:$0.48万
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财政年份:2005
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负责人:Stanley M. Spinola
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依托单位:
国内基金
海外基金
Journal of Integrative Plant Biology
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批准号:31024801
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项目类别:专项基金项目
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资助金额:24.0万元
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批准年份:2010
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负责人:贺萍
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依托单位: