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Extracellular Matrix Adhesins of Treponema pallidum

梅毒螺旋体细胞外基质粘附素

基本信息

批准号：
10531911
负责人：
CAROLINE E CAMERON
金额：
$ 26.33万
依托单位：
UNIVERSITY OF VICTORIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531911
关键词：
Address Adopted Affinity Animals Area Asia Australia Bacteria Bacterial Adhesins Binding Biological Assay Blood Circulation Blood Vessels Canada Cell physiology Cell-Matrix Junction Cells China Choline Cities Confocal Microscopy Congenital Syphilis Country Development Disease Disease Outbreaks Distant Early Diagnosis Endothelial Cells Endothelium Epidermal Growth Factor Epidermal Growth Factor Receptor Europe Exhibits Extracellular Matrix Extracellular Matrix Proteins Funding Goals HIV Immunize Income Individual Infection Infection prevention Invaded Investigation Knock-out Knowledge Laminin Receptor Life Style Ligands Mass Spectrum Analysis Maternal-Fetal Transmission Measures Membrane Membrane Microdomains Methodology Microscopy Molecular Neisseria meningitidis Neoplasm Metastasis North America Order Spirochaetales Organ Organism Pathogenesis Pathogenicity Pathway interactions Penicillins Platelet Activating Factor Prevalence Preventative vaccination Prevention strategy Process Proteins Proteomics Public Health Reporting Research Risk Role Signal Pathway Signal Transduction Site Structure Surface Syphilis Techniques Tissues Treponema pallidum Treponema pallidum adhesin Treponema pallidum subspecies pallidum United States Vaccine Design Vertical Disease Transmission cancer cell combat crosslink effective therapy fibulin insight low and middle-income countries men who have sex with men novel novel vaccines pathogen phosphoproteomics platelet activating factor receptor prevent programs receptor success syphilis vaccine transcriptome sequencing transmission process vaccine candidate

项目摘要

Project Summary/Abstract Syphilis remains a public health threat worldwide, with an estimated 11 million new infections per year and a global burden of 36 million infections. Within the last decade there have been outbreaks of syphilis cases in major cities around the world, including within the United States, Canada, Europe, Australia and China. A particularly sharp increase has been observed in men who have sex with men, with an alarming 56% increase observed since 2011. Syphilis infections increase the risk of acquiring and transmitting HIV, and there has been an 88% increase in congenital syphilis infections, resulting from mother to child transmission in utero, within the United States since 2012. Although syphilis is curable with penicillin treatment if diagnosed early, the worldwide syphilis prevalence shows that elimination of this disease will not occur through public health control measures alone, and instead will require development of effective strategies to prevent infection with this pathogen. Development of infection prevention strategies requires an in depth knowledge of the pathogenic mechanisms used by this highly successful pathogen. The bacterium that causes syphilis, Treponema pallidum, is able to disseminate rapidly within the host during the early stages of infection to infect every organ and tissue. Minimal understanding exists surrounding the pathogenic mechanisms used by T. pallidum to undergo widespread dissemination throughout the host, and gaining understanding within this highly relevant area of study will reveal novel vaccine candidates that can be targeted to prevent establishment of infection. The long-term objective of the studies contained in this proposal is to guide effective syphilis vaccine design by increasing our understanding of the pathogenic mechanisms used by T. pallidum to cause disease. To accomplish this objective, the following specific aims are proposed: (1) to investigate the interaction of the T. pallidum adhesin Tp0751 with the host endothelial proteins laminin receptor (LamR), stomatin, and epidermal growth factor-containing fibulin like extracellular matrix protein 1 (EFEMP1), which were identified as Tp0751-binding targets during the current funding period, as well as to investigate the interaction of T. pallidum with the endothelial receptor platelet activating factor receptor (PAFr) which is hypothesized to play a role in pathogenesis due to parallels with other invasive pathogens; (2) to determine the host endothelial cell signaling pathways activated by Tp0751 and T. pallidum to facilitate treponemal dissemination; and (3) to determine the functional consequence of Tp0751/T. pallidum engagement with host endothelial cells, at both the whole cell and molecular levels. These studies will increase understanding of the critical process of T. pallidum dissemination and are expected to reveal a novel pathogenic strategy of host signaling subversion used by T. pallidum to enable crossing of cellular barriers and accessing of deeper tissues within the host.

项目概要/摘要梅毒仍然是全世界的公共卫生威胁，估计每年有 1100 万新感染者，全球 3600 万人感染的负担。近十年来，梅毒病例暴发世界各地的主要城市，包括美国、加拿大、欧洲、澳大利亚和中国。一个男男性行为者的比例尤其急剧增加，达到令人震惊的 56% 自 2011 年以来观察到的增加。梅毒感染增加了感染和传播艾滋病毒的风险，并且由母婴传播导致的先天性梅毒感染增加了 88% 自 2012 年以来在美国境内，在子宫内。虽然梅毒可以通过青霉素治疗治愈，但如果如果及早诊断，全球梅毒流行情况表明这种疾病不会被消除仅通过公共卫生控制措施，而是需要制定有效的战略防止感染这种病原体。制定感染预防策略需要深入了解病原体这种非常成功的病原体所使用的机制。引起梅毒的细菌，密螺旋体梅毒螺旋体在感染早期能够在宿主体内迅速传播，从而感染所有宿主。器官和组织。围绕 T. 的致病机制，人们的了解还很有限。苍白球在整个宿主中广泛传播，并在此范围内获得理解高度相关的研究领域将揭示可用于预防的新型候选疫苗感染的建立。该提案中包含的研究的长期目标是指导有效的梅毒疫苗设计通过增加我们对梅毒螺旋体引起疾病的致病机制的了解。到为了实现这一目标，提出了以下具体目标：（1）研究T的相互作用。苍白球粘附素 Tp0751 与宿主内皮蛋白层粘连蛋白受体 (LamR)、气孔蛋白和含有表皮生长因子的纤维蛋白样细胞外基质蛋白 1 (EFEMP1)，已被鉴定作为当前资助期间 Tp0751 的结合目标，以及调查 T 的相互作用。苍白球与内皮受体血小板激活因子受体（PAFr）被假设发挥作用由于与其他侵入性病原体相似，因此在发病机制中发挥作用； (2)确定宿主内皮细胞由 Tp0751 和梅毒螺旋体激活的细胞信号通路促进密螺旋体传播；和（3）以确定 Tp0751/T 的功能结果。苍白球与宿主内皮细胞的接合，全细胞和分子水平。这些研究将增加对关键过程的理解梅毒螺旋体传播并有望揭示宿主信号传导的新致病策略梅毒螺旋体利用颠覆来跨越细胞屏障并进入更深的组织主人。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete.

DOI：
10.1038/s41598-017-01589-4
发表时间：
2017-05-08
期刊：
Scientific reports
影响因子：
4.6
作者：
Kao WA;Pětrošová H;Ebady R;Lithgow KV;Rojas P;Zhang Y;Kim YE;Kim YR;Odisho T;Gupta N;Moter A;Cameron CE;Moriarty TJ
通讯作者：
Moriarty TJ

Characterization of a novel family of fibronectin-binding proteins with M23 peptidase domains from Treponema denticola.