Placental Colonization by Treponema Pallidum, Congenital Syphilis & Novel Vaccine

梅毒螺旋体、先天性梅毒的胎盘定植

基本信息

批准号：
8819224
负责人：
GLABER ARTURO CENTURION-LARA
金额：
$ 38.54万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-18 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8819224
关键词：
Adherence Affect Animals Antibodies Antigens Bacteria Bacterial Adhesins Binding Binding Proteins Biological Assay Borrelia burgdorferi Cell Line Cells Child health care Chondroitin Sulfate A Chronic Disease Clinical Congenital Syphilis Coupled Data Dermatan Sulfate Development Diagnostic Disease Distant Epitopes Evaluation Exhibits Fetus Fibronectins Genes Genetic Glycosaminoglycans Goals Health Homologous Gene Immune response Immunity Immunization In Vitro Infant Infection Knowledge Laminin Lead Life Lipoprotein Binding Lipoproteins Low Birth Weight Infant Lyme Disease Malaria Maternal antibody Mediating Membrane Proteins Microtomy Modeling Molecular Molecular Conformation Morbidity - disease rate Mothers Newborn Infant Order Spirochaetales Organ Oryctolagus cuniculus Outcome Parasites Pathogenesis Perinatal mortality demographics Peru Placenta Plasmodium falciparum Pregnancy Outcome Pregnant Women Premature Birth Prevention Proteins Recombinant Proteins Recombinants Reporting Resources Role Sampling Spontaneous abortion Staging Surface Syphilis Syphilitic chancre System Testing Time Tissues Treponema pallidum Treponema pallidum adhesin Vaccines Variant Virulence Factors Virulent World Health Organization abortion adaptive immunity base congenital infection extracellular fetal gain of function gene discovery in vivo innovation mortality novel novel strategies novel vaccines outcome forecast pathogen prevent public health relevance research study stillbirth syphilis vaccine tool transmission process vaccine candidate vaccine development vector

项目摘要

DESCRIPTION (provided by applicant): An estimated >10 million new cases of syphilis occur worldwide every year with ~40% of congenital syphilis cases resulting in fetal loss or perinatal death. Moreover, approximately half of the surviving infants suffer serious sequelae. The successful control of syphilis requires a better understanding of critical virulence factors of Treponema pallidum, the syphilis spirochete, and additional knowledge of the antigenic markers of severe disease is warranted. Based upon our preliminary data, we hypothesize that (1) specific adhesins of T. pallidum are associated with invasion and colonization of placenta, (2) the presence of anti- adhesin maternal antibodies capable of blocking adherence might result in less severe or no congenital infections, and (3) these antigens could serve as vaccine candidates. Testing of this hypothesis will help achieve our long-term goals to understand congenital syphilis pathogenesis and develop effective vaccine. We propose to perform the first comprehensive molecular exploration of the role of three known and putative T. pallidum adhesins in congenital syphilis ex-vivo and in vivo, and to test the association of antibodies against these proteins with the congenital syphilis outcomes. Using a highly novel immunization approach, we will also assess the potential of these antigens as vaccine candidates in the rabbit infection model of syphilis. Due to the inability to cultivate T. pallidum in vitro, and its genetc intractability, we will employ several innovative approaches to perform our proposed studies. For instance, using a bioluminescent, non-infectious, non-adherent spirochete Borrelia burgdorferi to express T. pallidum genes, we discovered that T. pallidum TP0435 lipoprotein is a placental cell adhesin. We will also examine the role of two other putative placental adhesins, TP0954 and the laminin/fibronectin-binding lipoprotein TP0136. TP0954 exhibits similarity with the var2CSA domain of PfEMP1 of Plasmodium falciparum, which facilitates placental colonization by the malaria parasite causing great harm to the developing fetus. The goals of this project are to: determine the role of T. pallidum adhesins in binding to placental tissue usin a heterologous expression system (Aim 1); determine the impact of the adaptive immune response against syphilis in pregnant women on both placental colonization and on pregnancy outcomes (Aim 2); and determine whether specific adhesins or a combination of adhesins can be used as vaccine to induce protective immunity against syphilis (Aim 3). Significance. This application takes advantage of unique resources: clinical and molecular expertise of Dr. Centurion-Lara on treponemes and access to samples from syphilitic pregnant women in Peru for studying congenital syphilis, coupled with the experimental know-how and proficiency of using rabbit model of syphilis of Dr. Giacani along with the strong expertise of Dr. Parveen in spirochetes-host interactions. This will be the first such all-inclusive study that will enhance th understanding of congenital syphilis and will also lead to development of better diagnostic tools and vaccine strategy against syphilis.

描述（申请人提供）：全世界每年估计有超过 1000 万新发梅毒病例，其中约 40% 的先天性梅毒病例导致胎儿流产或围产期死亡，此外，大约一半的幸存婴儿患有严重的后遗症。控制梅毒需要更好地了解梅毒螺旋体的关键毒力因子，并且需要了解严重疾病的抗原标记物根据我们的初步数据，我们努力认为（1）梅毒螺旋体的特异性粘附素与胎盘的侵袭和定植有关，（2）能够阻断粘附的抗粘附素母体抗体的存在可能会导致不那么严重或没有先天性感染，并且（3）这些抗原可以作为候选疫苗，测试这一假设将有助于实现我们了解先天性梅毒发病机制和开发有效疫苗的长期目标。我们还将使用一种高度新颖的免疫方法，对三种已知和推定的梅毒螺旋体粘附素在先天性梅毒离体和体内抗体中的作用进行分子探索，并测试这些蛋白质与先天性梅毒结果的关联。评估这些抗原在兔梅毒感染模型中作为候选疫苗的潜力。由于无法在体外培养梅毒螺旋体，并且其遗传性难以控制，我们将评估这些抗原作为梅毒候选疫苗的潜力。采用多种创新方法来进行我们提出的研究，例如，使用生物发光、非传染性、非粘附螺旋体伯氏疏螺旋体来表达梅毒螺旋体基因，我们发现梅毒螺旋体TP0435脂蛋白是一种胎盘细胞粘附素。还检查了另外两种假定的胎盘粘附素 TP0954 和层粘连蛋白/纤连蛋白结合的作用脂蛋白 TP0136。TP0954 与恶性疟原虫 PfEMP1 的 var2CSA 结构域相似，可促进疟疾寄生虫在胎盘定植，对发育中的胎儿造成巨大伤害。该项目的目标是：确定梅毒螺旋体粘附素在结合中的作用。使用异源表达系统对胎盘组织进行检测（目标 1）；确定适应性免疫系统的影响；孕妇梅毒对胎盘定植和妊娠结局的反应（目标 2）；并确定是否可以使用特定粘附素或粘附素组合作为疫苗来诱导针对梅毒的保护性免疫（目标 3）。独特资源的优势：Centurion-Lara 博士在密螺旋体方面的临床和分子专业知识，以及获取秘鲁梅毒孕妇的样本以研究先天性梅毒梅毒，再加上 Giacani 博士使用兔梅毒模型的实验知识和熟练程度，以及 Parveen 博士在螺旋体与宿主相互作用方面的强大专业知识，这将是第一个此类全面的研究，将增强这一研究的成果。对先天性梅毒的了解也将导致开发更好的诊断工具和针对梅毒的疫苗策略。