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菌可引起一系列疾病，包括尿道炎和 宫颈炎，盆腔炎。感染建立的早期事件涉及相互作用 淋病奈瑟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招募。与生俱来的 免疫系统是抵御微生物入侵的第一道防线。 Toll 样受体 (TLR) 是一种 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质表达到不同的 专业和非专业免疫细胞学位。虽然吞噬细胞表达一系列 TLRs、粘膜上皮细胞表达更具选择性的指令集，限制了它们对某些物质做出反应的能力。 微生物配体。因此，它是上皮细胞和吞噬细胞对该病原体反应的协调 这会导致保护性免疫反应，从而清除细菌并解决感染。 我们的初步数据证明了细菌脂多糖（LPS）和 宿主 TLR4 在女性下生殖道 (FRT) 早期炎症反应中的作用。此外，我们 已经表明，近交小鼠品系在支持淋病奈瑟菌定植的能力方面存在差异，并且 诱导中性粒细胞流入。我们假设 TLR4 在专业吞噬细胞上表达 存在或招募到 FRT 在启动早期炎症反应中起着关键作用 负责淋病粘膜感染期间的细菌清除。此外，我们 相信其他宿主因素使受试者容易被淋病定植，并且 一些宿主可能比其他宿主更自然地抵抗感染。这种自然的基础 耐药性尚未明确，但可能是多基因的。 为了检验这些假设，我们提出以下三个具体目标：（1）确定是否自然 淋球菌脂多糖发生的突变可能是宿主炎症反应差异的原因 感染; (2) 确定 TLR4 接头 Mai 中的多态性是否可以解释 宿主对感染的炎症反应； (3) 确定抗感染的遗传基础 近交系小鼠品系。