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: 9128553
• 负责人: GLABER ARTURO CENTURION-LARA
• 金额: $ 66.32万
• 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/9128553
• 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; placental malaria; prevent; research study; 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（由适用提供）：估计估计> 1000万个新病例的梅毒病例每年发生，大约40％的先天性梅毒病例导致胎儿丧失或围产期死亡。此外，大约一半的生存婴儿遭受了严重的后遗症。梅毒的成功控制需要更好地了解毛颗粒的关键病毒因素，梅毒螺旋体，以及对严重疾病的抗原标志物的更多了解。基于我们的初步数据，我们假设（1）pallidum的特定依从性与摄入和定植的斑点有关，（2）能够阻止粘附的抗粘着蛋白抗体抗体的存在可能会导致不太严重或没有过过先天性的感染，并且这些抗原可能会作为疫苗来供电。对该假设的检验将有助于实现我们的长期目标，以了解先天性梅毒发病机理并开发有效的疫苗。我们建议对三种已知和假定的pallidum粘附剂在先天性梅毒前体和体内的作用进行第一次全面的分子探索，并测试针对这些蛋白质与先天性梅毒抗癌的抗体的关联。使用高度新颖的免疫体，我们还将评估这些抗原作为疫苗候选物的潜力。由于无法在体外培养粒子猪笼草及其基因棘手性，因此我们将采用几种创新的方法来执行我们的拟议研究。例如，使用生物发光的，非感染的，非粘附的螺旋体玻璃体伯氏毛毛毛毛毛毛孔基因，我们发现T. pallidum t. pallidum tp0435脂蛋白是斑点细胞粘附。我们还将研究另外两种假定的斑点粘合剂TP0954和层粘连蛋白/纤连蛋白结合脂蛋白TP0136的作用。 TP0954与恶性疟原虫的PFEMP1的VAR2CSA结构域相似，疟原虫由疟疾人寄生虫置换菌落，从而对发育中的胎儿造成巨大伤害。该项目的目标是：确定胶原链球菌粘附在与斑点组织结合的作用（AIM 1）；确定孕妇对梅毒对梅毒的适应性免疫激素对局部定植和妊娠结局的影响（AIM 2）；并确定是否可以将特定的粘附剂或粘附剂组合用作疫苗，以诱导对梅毒的保护性免疫（AIM 3）。意义。 This application takes advantage of unique resources: clinical and molecular expertise of Dr. Centurion-Lara on treponomes 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.这将是第一项全包研究，将增强对先天性梅毒的理解，还将导致开发更好的诊断工具和针对梅毒的疫苗策略。