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产生一系列疾病， 宫颈炎，到盆腔炎。感染建立的早期事件涉及相互作用 在N.淋病和粘膜上皮细胞，这导致粘膜表面的定植， 炎症介质的局部释放和专业免疫细胞的募集。先天 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 引导炎症反应的通路。这些生殖系编码的蛋白质表达为不同的 专业和非专业的免疫细胞。虽然吞噬细胞表达一系列的 粘膜上皮细胞表达更具选择性的库，这限制了它们对某些免疫应答的能力。 微生物配体因此，这是协调上皮细胞和吞噬细胞的反应，这种病原体 这导致保护性免疫反应，导致细菌清除和感染的解决。 我们的初步数据表明，细菌脂多糖（LPS）和 宿主TLR 4在女性下生殖道（FRT）早期炎症反应中的作用。而且我们 已经表明，近交系小鼠品系在支持N.淋病和 诱导中性粒细胞流入。我们推测TLR 4表达于专职吞噬细胞， 在FRT中存在或募集的细胞在启动早期炎症反应中起关键作用， 在淋病粘膜感染期间负责细菌清除。而且我们 认为其他宿主因素使受试者易受淋病定植，并且 有些宿主可能比其他宿主更能抵抗感染这种自然的基础 耐药性尚未确定，但可能是多基因的。 为了验证这些假设，我们提出了以下三个具体目标：（1）确定是否自然 淋球菌脂多糖发生突变可能是宿主炎症反应差异的原因， （2）为了确定TLR 4衔接子Mai的多态性是否可以解释感染中的差异， 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