Genetic variations in the innate immune response to Neisseria

对奈瑟菌的先天免疫反应的遗传变异

• 批准号: 7764289
• 负责人: Robin R Ingalls
• 金额: $ 37.93万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764289
• 关键词: Accounting; Acute; Cells; Cellular Structures; Cervicitis; Clinical; Data; Development; Disease; Endotoxins; Epithelial; Epithelial Cells; Event; Female; Genetic; Genetic Polymorphism; Genetic Variation; Genital system; Germ Lines; Gonorrhea; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Inbred BALB C Mice; Inbred Strains Mice; Infection; Infertility; Inflammation; Inflammation Mediators; Inflammatory Response; Integration Host Factors; Invaded; Lead; Ligands; Lipid A; Lipopolysaccharides; Mediator of activation protein; Modeling; Mus; Mutation; Natural Resistance; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Organism; Pattern; Pelvic Inflammatory Disease; Phagocytes; Play; Predisposition; Process; Proteins; Recruitment Activity; Reporting; Resistance; Resistance to infection; Resolution; Role; Sexually Transmitted Diseases; Signal Transduction; Signal Transduction Pathway; Structure; Surface; Symptoms; TLR4 gene; Testing; Toll-like receptors; Urethritis; Vaccines; Variant; Virulence; Woman; base; chemokine; cytokine; in vivo; macrophage; microbial; microorganism; mouse model; neutrophil; pathogen; reproductive; response; therapy development

The human pathogen Neisseria gonorrhoeae produces an array of diseases ranging from urethritis and cervicitis, to pelvic inflammatory disease. Early events in the establishment of infection involve interactions between N. gonorrhoeae and mucosal epithelial cells, which leads to colonization of the mucosal surface, the local release of inflammatory mediators, and the recruitment of professional immune cells. The innate immune system is the first line of defense against invading microorganisms. Toll-like receptors (TLRs) are a part of this innate immune defense, recognizing conserved microbial patterns and initiating signal transduction pathways that direct the inflammatory response. These germ-line encoded proteins are expressed to varying degrees in both professional and non-professional immune cells. While phagocytic cells express an array of TLRs, mucosal epithelial cells express a more selective repertoire that limits their ability to respond to some microbial ligands. Thus, it is the coordination of epithelial and phagocytic cell responses to this pathogen that results in the protective immune response that leads to bacterial clearance and resolution of infection. Our preliminary data demonstrates a role for interactions between bacterial lipopolysaccharide (LPS) and host TLR4 in the early inflammatory response of the lower female reproductive tract (FRT). Furthermore, we have shown that inbred mouse strains differ in their ability to support colonization with N. gonorrhoeae and induce a neutrophil influx. We hypothesize that TLR4 expressed on professional phagocytic cells present or recruited to the FRT plays a key role in initiating the early inflammatory response that is responsible for bacterial clearance during mucosal infections with gonorrhea. Furthermore, we believe additional host factors render the subject susceptible to colonization with gonorrhea, and that some hosts may be more naturally resistant than others to infection. The basis of this natural resistance is yet undefined, but is likely to be multigenic. In order to test these hypotheses we propose the following three Specific Aims: (1) To determine if naturally occurring mutations in gonococcal LPS might account for differences in the host inflammatory response to infection; (2) To determine if polymorphisms in the TLR4 adaptor Mai might account for differences in the host inflammatory response to infection; and (3) To detemnine the genetic basis for resistance to infection in inbred mouse strains.

人类病原体淋病奈瑟氏菌会产生一系列疾病，包括尿道炎和 宫颈炎，骨盆炎性疾病。建立感染的早期事件涉及互动 在淋病链球菌和粘膜上皮细胞之间，导致粘膜表面定植 炎症介质的局部释放以及专业免疫细胞的募集。先天 免疫系统是针对入侵微生物的第一道防线。 Toll样受体（TLR）是一个 这种先天免疫防御的一部分，识别保守的微生物模式并启动信号转导 指导炎症反应的途径。这些种系编码的蛋白表示为变化 专业和非专业免疫细胞的学位。吞噬细胞表达 TLR，粘膜上皮细胞表达更具选择性的曲目，限制了它们对某些响应的能力 微生物配体。因此，这是上皮和吞噬细胞对这种病原体的反应的协调 这导致了保护性免疫反应，从而导致细菌清除和感染的分辨率。 我们的初步数据证明了细菌脂多糖（LPS）和 在下部女性生殖道（FRT）的早期炎症反应中，宿主TLR4。此外，我们 已经表明，近交小鼠的菌株在支持淋病猪笼草的定植能力上有所不同 诱导中性粒细胞涌入。我们假设在专业吞噬细胞上表达的TLR4 出席或招募FRT在发起早期炎症反应中起关键作用 在淋病感染期间，负责细菌清除。此外，我们 相信其他宿主因素使受试者容易被淋病定殖，并且 某些宿主可能比其他宿主更自然地抵抗感染。这个自然的基础 阻力尚未定义，但可能是多基因的。 为了检验这些假设，我们提出以下三个特定目的：（1）确定自然是否自然 淋球菌LPS中发生突变可能是宿主炎症反应的差异 感染; （2）确定TLR4适配器中的多态性是否可能解释 宿主对感染的炎症反应； （3）确定抗抗性感染的遗传基础 近交小鼠菌株。