Borrelia burgdorferi Interactions with Mammalian Host Cells

伯氏疏螺旋体与哺乳动物宿主细胞的相互作用

• 批准号: 7901127
• 负责人: Janakiram Seshu
• 金额: $ 34.36万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901127
• 关键词: Adherence; Arginine; Arthropods; Bacteria; Bacteria oligopeptide permease; Base Sequence; Binding; Bite; Borrelia; Borrelia burgdorferi; C-terminal; Case Study; Cells; Characteristics; DBL Oncoprotein; Gene Expression; Genes; Glutamic Acid; Glycine; Infection; Integrins; Length; Lyme Disease; Mammalian Cell; Mammals; Modeling; Morbidity - disease rate; Mus; N-terminal; Open Reading Frames; Plasmids; Proteins; Public Health; RGD (sequence); Recombinants; Role; Signal Transduction; Structure; Surface; Ticks; Tissues; United States; base; genome-wide; mutant; pathogen; response; transmission process; vector

DESCRIPTION (provided by applicant): Lyme disease, caused by the spirochetal bacterium Borrelia burgdorferi, is the most prevalent arthropod-borne infection in the United States and has been classified as a re-emerging vector-borne infection due to a significant increase in the number of reported cases. Lyme disease is an important public health issue, particularly in endemic states where it contributes to significant rates of morbidity. The ability of B. burgdorferi to cause infection in mammals is dependent on its ability to alter gene expression rapidly in response to highly disparate environmental signals that it encounters upon transmission through a tick bite. Several genome-wide transcriptional analyses, comparing B. burgdorferi cultivated under conditions that mimic the tick vector or the mammalian host, revealed that several plasmid encoded genes on linear plasmid 54 (Ip54) are up-regulated under mammalian host-specific conditions. Sequence based secondary structure analysis of several of these differentially expressed ORFs revealed that BBA34 has an arginine-glycine-glutamic acid (RGD) motif at the N-terminal region and that this motif is probably surface-exposed. Moreover, based on sequence similarity, BBA34 is an orthologue of oligopeptide permease A (OppA5) protein but does not bind heptapeptides like other chromosomally encoded OppA orthologues and is up-regulated in B. burgdorferi upon transmission to mammalian host. The objective of this proposal is to determine if the RGD motif on BBA34 will facilitate interactions with mammalian cells presumably through direct interactions with integrins. The first specific aim is to determine the interactions of recombinant BBA34 proteins with various integrins either purified or expressed on mammalian cells. We will determine the role of RGD motif in binding to various integrins using full-length, N-terminal and C-terminal recombinant BBA34 proteins. The second specific aim is to determine the binding, infectivity and tissue dissemination characteristics of a bba34- mutant of B. burgdorferi in the murine model of Lyme disease. The third specific aim is to characterize the binding and infectivity of bba34-/bbk32- and bba34-/p66- double mutants of B. burgdorferi in the murine model of Lyme disease. We will determine the significance of the loss of multiple borrelial determinants on host-cell adherence. These studies will help to determine the host-pathogen interactions that are critical for the colonization of the mammalian host by B. burgdorferi.

描述（由申请人提供）：莱姆病，由螺旋体细菌伯氏疏螺旋体引起，是美国最常见的节肢动物传播感染，由于报告病例数量的显著增加，已被归类为再次出现的媒介传播感染。莱姆病是一个重要的公共卫生问题，特别是在莱姆病流行的国家，它造成了很高的发病率。伯氏疏螺旋体在哺乳动物中引起感染的能力取决于它在通过蜱叮咬传播时遇到的高度不同的环境信号，并根据这些信号迅速改变基因表达的能力。几种全基因组转录分析，比较了在模拟蜱虫媒介和哺乳动物宿主条件下培养的伯氏疏螺旋体，揭示了在哺乳动物宿主特异性条件下，线性质粒54 （Ip54）上的几个质粒编码基因上调。基于序列的二级结构分析显示，BBA34在n端有一个精氨酸-甘氨酸-谷氨酸（RGD）基序，该基序可能是表面暴露的。此外，基于序列相似性，BBA34是寡肽渗透酶A （OppA5）蛋白的同源物，但不像其他染色体编码的OppA同源物那样结合七肽，并且在伯氏疏螺旋体中传播到哺乳动物宿主后上调。

项目成果

Overexpression of CsrA (BB0184) alters the morphology and antigen profiles of Borrelia burgdorferi.

CsrA (BB0184) 的过度表达会改变伯氏疏螺旋体的形态和抗原谱。

• DOI: 10.1128/iai.00673-09
• 发表时间: 2009
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Sanjuan,Eva;Esteve-Gassent,MariaD;Maruskova,Mahulena;Seshu,J
• 通讯作者: Seshu,J

Borrelia host adaptation Regulator (BadR) regulates rpoS to modulate host adaptation and virulence factors in Borrelia burgdorferi.

• DOI: 10.1111/mmi.12171
• 发表时间: 2013-04
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Miller CL;Karna SL;Seshu J
• 通讯作者: Seshu J

Statins reduce spirochetal burden and modulate immune responses in the C3H/HeN mouse model of Lyme disease.

他汀类药物减轻了螺旋体负担，并调节莱姆病的C3H/Hen小鼠模型中的免疫反应。

• DOI: 10.1016/j.micinf.2016.03.004
• 发表时间: 2016-06
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Van Laar TA;Hole C;Rajasekhar Karna SL;Miller CL;Reddick R;Wormley FL;Seshu J
• 通讯作者: Seshu J

Effect of levels of acetate on the mevalonate pathway of Borrelia burgdorferi.

• DOI: 10.1371/journal.pone.0038171
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Van Laar TA;Lin YH;Miller CL;Karna SL;Chambers JP;Seshu J
• 通讯作者: Seshu J

Deletion of BBA64, BBA65, and BBA66 loci does not alter the infectivity of Borrelia burgdorferi in the murine model of Lyme disease.

BBA64、BBA65 和 BBA66 位点的删除不会改变莱姆病小鼠模型中伯氏疏螺旋体的感染性。

• DOI: 10.1128/iai.00803-08
• 发表时间: 2008
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Maruskova,Mahulena;Seshu,J
• 通讯作者: Seshu,J