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.