Mechanisms of Gonococcal Pilin Antigenic and Phase Variation

淋球菌菌毛蛋白抗原和相变的机制

基本信息

批准号：
8792357
负责人：
Hank S. SEIFERT
金额：
$ 38.63万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792357
关键词：
Adherence Amino Acid Sequence Antigenic Diversity Antigenic Variation Bacteria Bacterial Chromosomes Bacterial Meningitis Bacterial Pili Binding Proteins Biological Models Borrelia Cell physiology Chromosomes Conversion disorder DNA DNA Damage DNA Repair DNA Sequence DNA Structure DNA biosynthesis Diploidy Disease Enterobacteriaceae Epididymitis Event Evolution Fimbriae Proteins Frequencies Funding Gene Conversion Generations Genes Genetic Recombination Genetic Transcription Genome Stability Genomics Gonorrhea Grant Guanine Health Host Defense Human Immune Immune system Immunoglobulins Individual Infant Infection Investigation Life Malignant - descriptor Mammalian Cell Measures Mediating Meninges Meningitis Modeling Molecular Mutation Mycoplasma Nasopharynx Neisseria Neisseria gonorrhoeae Neisseria meningitidis Neuraxis Oncogenes Organism Outcome Parasites Pathogenesis Pelvic Inflammatory Disease Phase Pilum Play Population Process Property Protein Binding Proteins RNA-Binding Proteins Recording of previous events Role Sexually Transmitted Diseases Small RNA Structure Surface Antigens System T-Cell Receptor Teenagers Testing Treponema pallidum Variant Virulence Factors Woman Work base cell type fungus helicase high risk innovation loss of function mutation male malignant state men nucleic acid structure pathogen pressure prevent programs recombinational repair telomere young adult

项目摘要

DESCRIPTION (provided by applicant): The pathogenic Neisseria are obligate human pathogens that rely on several antigenic variation systems to continually colonize and cause disease in the human population. This proposal will further our studies into the molecular mechanisms used to allow pilin antigenic variation in Neisseria gonorrhoeae. High frequency changes in the pilin amino acid sequence are mediated by gene conversion reactions between one of 18 silent pilin copies and the single expressed pilin gene. In the past funding period, we have identified most of the proteins involved in this process and have demonstrated that the pathogenic Neisseria carry diploid chromosomes that may facilitate gene conversion. We have additionally shown that both the formation of an alternative DNA structure called a guanine quartet (G4), and the transcription of a small RNA within the G4 are required for pilin antigenic variation. In the next funding period we will determine the role of G4 transcription during pilin antigenic variation. Proteins that bind the G4 structure will be identified and we will test whethe these proteins stimulate G4 structure formation or dissolution, and/or the process of pilin antigenic variation. We will also determine whether the G4 structure acts to promote recombination by blocking DNA replication and whether specific helicases prevent a replication stall. We will probe for formation of the G4 structure within the bacterial chromosome and determine whether the G4 structure associates with other DNA sequences. Finally, the effect of various partial loss-of-function mutations on pilin antigenic variation will be determined. The results of these innovative studies will have great impact on the study of Neisserial pathogenesis, mechanisms of antigenic variation, DNA recombination and replication, and the role of alternative DNA structures on molecular processes in many cell types.

描述（由申请人提供）：致病性奈瑟氏菌是依赖几种抗原变异系统的强制性病原体，以持续定殖并引起人口疾病。该建议将进一步研究用于促进淋病奈瑟氏菌的抗原抗原变异的分子机制。 PILIN氨基酸序列的高频变化是由18个无声PILIN拷贝和单个表达的PILIN基因之间的基因转化反应介导的。在过去的资金期间，我们已经确定了这一过程中涉及的大多数蛋白质，并证明了病原性奈瑟氏菌携带二倍体染色体，这些染色体可能促进基因转化。我们还表明，称为鸟嘌呤四重奏（G4）的替代DNA结构的形成，以及G4中小RNA的转录是PILIN抗原变异所必需的。在下一个资金期间，我们将确定G4转录在PILIN抗原变异期间的作用。将确定结合G4结构的蛋白质，我们将测试这些蛋白质刺激G4结构形成或溶解和/或PILIN抗原变异的过程。我们还将确定G4结构是否通过阻断DNA复制以及特定的解旋酶是否阻止复制失速来促进重组。我们将探测细菌染色体内G4结构的形成，并确定G4结构是否与其他DNA序列相关。最后，将确定各种部分功能丧失突变对PILIN抗原变异的影响。这些创新研究的结果将对奈瑟氏发病机理，抗原变异机制，DNA重组和复制的机制以及替代DNA结构在许多细胞类型的分子过程中的作用产生重大影响。