Chlamydia virulence: exploitation of host N-glycosylation

衣原体毒力：利用宿主 N-糖基化

基本信息

批准号：
8753572
负责人：
LEE ANN CAMPBELL
金额：
$ 38.63万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8753572
关键词：
Acute Adhesives Antibiotics Bacteria Bacterial Proteins Birds Blindness Campylobacter Cardiovascular Diseases Catalytic Domain Cells Characteristics Chinese Hamster Ovary Cell Chlamydia Chlamydia Infections Chlamydia trachomatis Chlamydophila pneumoniae Chlamydophila psittaci Chronic Complex Confocal Microscopy Development Disease Ectopic Pregnancy Endoplasmic Reticulum Excision Foundations Future Genital system Genome Genomics Golgi Apparatus Grant Health Helicobacter Homologous Gene Human IGF Type 2 Receptor Immune response Immunobiology In Vitro Infection Infection prevention Infertility Integration Host Factors Intervention Laboratories Ligands Link Low income Lung Mannose Maps Mechanics Microscopy Morbidity - disease rate Oligosaccharides Organism Pathway interactions Pattern Pelvic Inflammatory Disease Play Pneumonia Polysaccharides Prevention Prevention therapy Preventive Intervention Process Proteins Proteomics Psittacosis Recruitment Activity Reporting Research Sexually Transmitted Diseases Small Interfering RNA Structure Testing Therapeutic Transferase United States Vaccines Vacuole Vagina Validation Virulence Virulence Factors Western World Woman cell type genital infection global health glycosylation in vivo inhibitor/antagonist knock-down major outer membrane protein mannose receptor mortality mouse model mutant novel novel strategies obligate intracellular parasite pathogen prevent receptor research study respiratory sugar trafficking

项目摘要

DESCRIPTION (provided by applicant): Chlamydial infections have significant impact on human health. Chlamydia trachomatis is the leading cause of sexually transmitted disease in the United States and preventable blindness in low income nations. In women, the consequences of untreated infection with C. trachomatis can be severe resulting in pelvic inflammatory disease, tubal factor infertility and ectopic pregnancy. Despite significant advances in understanding the immunobiology of chlamydial infection, there are no vaccines available. Although antibiotics are effective in treating acute infections, asymptomatic infection is common and chronic infections are difficult to treat. Thus, elucidating the interactions of this obligate intracellular parasite with the host is fundamental to identifying novel strategies for prevention intervention. A major research focus in our laboratory has been on chlamydial ligand/host receptor interactions. To this end, we have determined that the chlamydial glycan, which is an N- linked high mannose oligosaccharide on the major outer membrane protein (MOMP), plays a key role in attachment and infectivity through interaction with the host mannose receptor. Significantly, removal of the glycan or pretreatment with mannose oligosaccharides to interfere with attachment of the organism to the host significantly decreases infectivity and lung burden or shedding in mouse models of lung and genital tract infections, respectively. These findings support the potential for development of "anti-adhesive therapy" for prevention of infection. An alternative or complementary approach would be to prevent glycosylation of the chlamydial MOMP. The structure of the Chlamydia glycan is analogous to the N-glycans produced by the highly ordered N-glycosylation process in the host. At either the genomic or proteomic level, no chlamydial homologs have been found for the requisite proteins for N-glycosylation. Supported by these observations, the hypothesis to be tested is that the chlamydial MOMP is glycosylated by the host machinery and that Chlamydia recruits the machinery to the vacuole within the host that it resides. A corollary to this hypothesis that will be tested is that inhibitors of host N-glycosylation that inhibit chlamydial infectivity in vitro will decrease lung burden or vaginal shedding in mouse models of lung infection and genital tract infection, respectively. These studies may provide the foundation for development of future strategies to interfere with chlamydial infection.

描述（由申请人提供）：沙眼衣原体感染对人类健康具有重大影响，是美国性传播疾病的主要原因，也是低收入国家女性可预防性失明的主要原因。尽管在了解衣原体感染的免疫生物学方面取得了重大进展，但可能会严重导致盆腔炎、输卵管因素不孕和宫外孕。尽管抗生素可以有效治疗急性感染，但无症状感染很常见，而且慢性感染很难治疗，因此，阐明这种专性细胞内寄生虫与宿主的相互作用对于确定新的预防干预策略至关重要。我们实验室的主要研究重点是衣原体配体/宿主受体相互作用。为此，我们确定了衣原体聚糖，它是主要外膜上的N-连接高甘露糖寡糖。蛋白（MOMP）通过与宿主甘露糖受体相互作用在附着和感染性中发挥关键作用。值得注意的是，去除聚糖或用甘露寡糖预处理以干扰生物体与宿主的附着可显着降低感染性和肺负荷或脱落。分别在肺部和生殖道感染的小鼠模型中，这些发现支持了开发“抗粘附疗法”来预防感染的潜力。衣原体 MOMP 的结构类似于宿主中高度有序的 N-糖基化过程产生的 N-聚糖，在基因组或蛋白质组水平上，尚未发现衣原体所需蛋白质的同源物。 N-糖基化得到这些观察结果的支持，需要检验的假设是衣原体 MOMP 被宿主机器糖基化，并且衣原体将机器招募到其所在宿主内的液泡中，将要测试的这一假设的推论是，在体外抑制衣原体感染的宿主 N-糖基化抑制剂将减少肺部感染小鼠模型中的肺部负担或阴道脱落。这些研究可能为制定未来干扰衣原体感染的策略奠定基础。