Placental Colonization by Treponema Pallidum, Congenital Syphilis & Novel Vaccine

梅毒螺旋体、先天性梅毒的胎盘定植

• 批准号: 9197601
• 负责人: GLABER ARTURO CENTURION-LARA
• 金额: $ 65.94万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 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/9197601
• 关键词: Adherence; Affect; Animals; Antibodies; Antigens; Bacteria; Bacterial Adhesins; Binding; Binding Proteins; Biological Assay; Borrelia burgdorferi; Cell Line; Cells; Child health care; Chronic Disease; Clinical; Congenital Syphilis; Coupled; Data; Dermatan Sulfate; Development; Diagnostic; Disease; Distant; Epitopes; Evaluation; Exhibits; Fetus; Fibronectins; Genes; Genetic; Goals; Health; Homologous Gene; Immune response; Immunity; Immunization; Immunize; In Vitro; Infant; Infection; Knowledge; Laminin; Lead; 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; Physiological; Placenta; Plasmodium falciparum; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevention; Proteins; Recombinant Proteins; Recombinants; Reporting; Resources; Role; Sampling; Spontaneous abortion; Surface; Syphilis; Syphilitic chancre; System; Testing; Tissues; Treponema pallidum; Vaccines; Variant; Virulence Factors; Virulent; World Health Organization; abortion; adaptive immune response; base; chondroitin sulfate glycosaminoglycan; congenital infection; experimental study; extracellular; fetal; gain of function; in vivo; innovation; mortality; novel; novel strategies; novel vaccines; outcome forecast; pathogen; placental malaria; prevent; public health relevance; stillbirth; syphilis vaccine; tool; transmission process; vaccine candidate; vaccine development; vector

 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(由申请人提供)：据估计，全世界每年新增梅毒病例1000万例，其中约40%的先天性梅毒病例会导致胎儿丧失或围产儿死亡。此外，大约一半幸存的婴儿患有严重的后遗症。梅毒的成功控制需要更好地了解梅毒螺旋体梅毒的关键毒力因素，以及对严重疾病的抗原标记的更多了解。根据我们的初步数据，我们假设(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)抗粘附素母体抗体的存在可能导致较轻的或没有先天性感染，以及(3)这些抗原可以作为疫苗候选。对这一假说的验证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。我们建议对三种已知和推定的梅毒螺旋体粘附素在体外和体内先天性梅毒中的作用进行首次全面的分子探索，并测试针对这些蛋白的抗体与先天性梅毒结局的相关性。使用一种高度新颖的免疫方法，我们还将评估这些抗原作为梅毒兔感染模型候选疫苗的潜力。由于无法在体外培养梅毒螺旋体，以及它的基因组等难题，我们将采用几种创新的方法来进行我们拟议的研究。例如，利用生物发光、非传染性、非粘附性的伯氏疏螺旋体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。我们还将研究另外两个推测的胎盘粘附素，TP0954和层粘连蛋白/纤维连接蛋白结合脂蛋白TP0136的作用。TP0954与恶性疟原虫PfEMP1基因的var2CSA结构域具有相似性，有利于疟疾原虫的胎盘定植，对发育中的胎儿造成极大的伤害。该项目的目标是：确定梅毒螺旋体粘附素在异源表达系统中与胎盘组织结合的作用(目标1)；确定孕妇对梅毒的适应性免疫反应对胎盘定植和妊娠结局的影响(目标2)；以及确定特定的粘附素或粘附素的组合是否可用作疫苗来诱导梅毒的保护性免疫(目标3)。意义重大。这一应用程序利用了独特的资源：Centurion-Lara博士在密螺旋体方面的临床和分子专业知识，用于研究先天性梅毒的秘鲁梅毒孕妇样本的获取，Giacani博士使用兔梅毒模型的实验技术和熟练程度，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。这将是第一次这样的全方位研究，将加强对先天性梅毒的了解，并将导致开发更好的诊断工具和梅毒疫苗战略。