Rickettsia-host interface and multiple paths to invasion
Rickettsia-host interface and multiple paths to invasion
批准号:
9196051
负责人:
Abdu F Azad
金额:
$55.89万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-15 至 2021-05-31
关键词:
ActinsAdherenceAdhesionsAfricaArthropodsBacterial AdhesinsBiologyBioterrorismBoutonneuse FeverCell AdhesionCellsCentral AmericaComplexCytolysisCytoplasmCytoskeletonDataDiseaseDockingDrug DesignEarly EndosomeEmerging Communicable DiseasesEndemic Flea-Borne TyphusEndocytosisEndothelial CellsEpithelialEukaryotic CellEuropeFMNL1 geneFamilyFeverFleasFoundationsGenesGenomeGenomicsGenotypeGenus FelisGoalsGrowthInfectionInsectaIntegrinsInterventionInvertebratesKnowledgeLeadLigandsLinkMediatingMembraneMembrane ProteinsMetabolismMiddle EastModalityMolecularMorbidity - disease rateOutcomeParasitesPathogenesisPhagocytosis InductionPhagosomesPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhospholipasePhylogenetic AnalysisProcessProteinsPublic HealthReceptor SignalingResearchRickettsiaRickettsia InfectionsRickettsia rickettsiiRocky Mountain Spotted FeverRoleSerine ProteaseSignal TransductionSignal Transduction PathwaySiteSouth AmericaSpottingsSurface AntigensTestingTherapeuticTherapeutic InterventionTyphusVaccinesVariantWorkanalogcombatcomparativedesigndisease phenotypeeffective interventioninterestinvertebrate hostmortalitynovelpathogenprotein functionreceptorsecretory proteintransmission processuptakevaccine developmentweapons
中文摘要
立克次体感染的全球影响从长期已知的
病原体,以及新发现的病原体的出现。感染:
里氏立克次体(落基山斑点热病)在#年继续流行,后果严重。
南美洲和中美洲。年康诺里杆菌(地中海斑点热病)卷土重来
欧洲、中东和非洲,以及最近全球范围内小鼠斑疹伤寒(R.
伤寒杆菌),突出了立克次体疾病的威胁。尽管对公众健康的重要性
致病立克次体,我们对立克次体生物学的有限知识一直是一个
这是朝着更有效的干预方式取得进展的障碍。我们的系统发育学
分析强调了立克次体基因组的相当大的变异,提供了一种
将特定的基因类型与其相关的疾病表型联系起来的框架。对于几个人来说
在普遍的立克次体过程中已被表征的真正的分泌蛋白
(即宿主细胞的黏附、侵袭和细胞内的生长和存活),一个斑驳的基因组
分布表明,支撑这些过程的机制是内在的
立克次体各不相同。例如,我们最近在斑疹伤寒(斑疹伤寒群)上的工作
发现了一种新的invasin,Ralf,它在依赖于宿主的过程中与宿主Arf6相互作用
磷脂酰肌醇PIP2。奇怪的是,斑点热病的物种中缺少Ralf基因
组(SFG)。相反,SFG的两个特性良好的表面蛋白(Sca0和Sca2)
在非SFG立克次体中,病原体要么不存在(Sca0),要么高度分化(Sca2)。
因此,立克次体侵袭宿主细胞的机制比以前更加复杂
赞赏,因此有必要采用比较的方法来调查
支持发病的因素。根据这项建议,我们的工作将集中于确定
Sca3和Sca2(d-sca2)蛋白的哺乳动物和无脊椎动物宿主细胞靶标
来自非SFG物种(目标1)。此外,我们将调查非
SFG物种触发磷脂酰肌醇(PIP)代谢,促进膜褶皱和
立克次体内吞作用,早期内吞体上存在已鉴定的宿主蛋白和PIP
进一步探索作为介导噬菌体的立克次体磷脂酶的对接位置
逃生(目标2)。这项工作的成功结果将为如何
不同的立克次体利用不同的分子实现普遍的立克次体
通过诱导吞噬作用感染宿主细胞质的过程。我们预料到了这一点
提供针对疾病的治疗方法以对抗致命性立克次体的知识。
英文摘要
The global impact of rickettsial infections is illustrated by the resurgence of long-known
pathogens, as well as the emergence of newly recognized pathogens. Infections with
Rickettsia rickettsii (Rocky Mountain Spotted Fever) continue with severe consequences in
South and Central America. The resurgence of R. conorii (Mediterranean Spotted Fever) in
Europe, the Middle East and Africa, as well as a recent worldwide rise in murine typhus (R.
typhi), highlights the threats of rickettsial diseases. Despite the public health importance of
pathogenic Rickettsia spp.,, our limited knowledge of ricketsial biology has been an
impediment to progress towards more effective intervention modalities. Our phylogenomics
analyses have highlighted considerable variation across Rickettsia genomes, providing a
framework to link particular genotypes with their associated disease phenotypes. For several
bona fide secretory proteins that have been characterized in universal rickettsial processes
(i.e., host cell adhesion, invasion and intracellular growth and survival), a patchy genomic
distribution indicates that the mechanisms underpinning these processes are inherently
different across rickettsial groups. For instance, our recent work on R. typhi (Typhus Group)
identified a novel invasin, RalF, which interacts with host Arf6 in a process dependent on host
phosphoinositide PIP2. Curiously, RalF genes are absent from species of Spotted Fever
Group (SFG). Conversely, two well-characterized surface proteins (Sca0 and Sca2) of SFG
pathogens are either absent (Sca0) or highly divergent (Sca2) in non-SFG rickettsial species.
Thus, mechanisms of Rickettsia host cell invasion are more complex than previously
appreciated, necessitating the need to employ a comparative approach for investigating the
factors underpinning pathogenesis. Under this proposal, our work will focus on identifying the
mammalian and invertebrate host cell targets of Sca3 and divergent Sca2 (d-Sca2) proteins
from non-SFG species (Aim 1). Additionally, we will investigate the manner by which non-
SFG species trigger phosphoinositide (PIP) metabolism to facilitate membrane ruffling and
rickettsial endocytosis, with identified host proteins and PIPs present on the early endosome
further explored as docking sites for rickettsial phospholipases that mediate phagosome
escape (Aim 2). The successful outcome of this work will provide important clues on how
divergent Rickettsia species utilize different molecules to achieve the universal rickettsial
process of host cytoplasmic infection via induction of phagocytosis. We anticipate this
knowledge to yield disease-specific therapeutic approaches to combat fatal rickettsioses.
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会议论文
Rickettsia-host interface and multiple paths to invasion
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批准号:10359124
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项目类别:
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资助金额:$66.25万
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财政年份:2016
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负责人:Abdu F Azad
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依托单位:
Rickettsia-host interface and multiple paths to invasion
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Murine Typhus: Vector Biology and Transmission
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批准号:8150061
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资助金额:$30.4万
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Rickettsia felis & other emerging rickettsial pathogens
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批准号:7256041
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资助金额:$37.13万
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财政年份:2006
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依托单位:
Generation of Genetically Attenuated Rickettsiae
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批准号:7171592
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资助金额:$41.17万
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财政年份:2005
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依托单位:
Generation of Genetically Attenuated Rickettsiae
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资助金额:$41.22万
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Generation of Genetically Attenuated Rickettsiae
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资助金额:$42.58万
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财政年份:2005
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Generation of Genetically Attenuated Rickettsiae
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资助金额:$41.47万
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财政年份:2005
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依托单位:
Generation of Genetically Attenuated Rickettsiae
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批准号:6979743
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资助金额:$40.04万
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财政年份:2005
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负责人:Abdu F Azad
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BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES
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BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES
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资助金额:$43.89万
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BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES
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BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES
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资助金额:$43.89万
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BIOLOGY AND IMMUNOLOGY OF MALARIA PARASITE LIVER-STAGES
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批准号:6892768
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资助金额:$4.58万
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财政年份:2000
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负责人:Abdu F Azad
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依托单位:
INTERSPECIFIC COMPETITION BETWEEN RICKETTSIAE IN TICKS
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批准号:6362350
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项目类别:
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资助金额:$19.08万
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财政年份:1998
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负责人:Abdu F Azad
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依托单位:
INTERSPECIFIC COMPETITION BETWEEN RICKETTSIAE IN TICKS
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批准号:7433276
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项目类别:
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依托单位:
海外基金