Chlamydia virulence: exploitation of host N-glycosylation

 描述(申请人提供)：衣原体感染对人类健康有重大影响。沙眼衣原体是美国性传播疾病的主要原因，在低收入国家是可预防的失明。在妇女中，沙眼衣原体感染未经治疗的后果可能是严重的，导致盆腔炎、输卵管因素不孕和异位妊娠。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，但目前还没有可用的疫苗。尽管抗生素对治疗急性感染有效，但无症状感染很常见，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预防干预的新策略是至关重要的。我们实验室的一个主要研究重点是衣原体配体/宿主受体的相互作用。为此，我们已经确定衣原体多糖是主要外膜蛋白(MOMP)上的一种N-连接的高甘露糖低聚糖，通过与宿主甘露糖受体的相互作用在附着和感染性中发挥关键作用。值得注意的是，在肺部和生殖道感染的小鼠模型中，去除多糖或用甘露寡糖预处理以干扰有机体与宿主的附着显著降低了感染性和肺负担或脱落。这些发现支持了“抗粘连疗法”用于预防感染的发展潜力。另一种替代或补充的方法是防止衣原体MOMP的糖基化。衣原体多糖的结构类似于宿主体内高度有序的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N-糖基化所需蛋白质的衣原体同源物。在这些观察的支持下，需要检验的假设是，衣原体MOMP被宿主机械糖基化，衣原体将机械招募到其所在宿主内的液泡中。这一假说的一个推论是，在体外抑制衣原体感染性的宿主N-糖基化抑制剂将分别减少肺部感染和生殖道感染小鼠的肺负担或阴道脱落。这些研究可能为未来制定干预衣原体感染的策略提供基础。

 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.