Pathogenomics of Chlamydial Infection

衣原体感染的病理基因组学

• 批准号: 6809067
• 负责人: HARLAN D CALDWELL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6809067
• 关键词: Chlamydia trachomatis; Chlamydiaceae; bacteria infection mechanism; bacterial genetics; confocal scanning microscopy; functional /structural genomics; genetic regulation; host organism interaction; interferon gamma; microarray technology; polymerase chain reaction; protein biosynthesis; proteomics; regulatory gene; sexually transmitted diseases; tissue /cell culture

Chlamydia trachomatis is the leading cause of preventable blindness and a major cause of sexually transmitted disease. Chlamydiae are obligate intracellular bacteria that are characterized by their unique complex biphasic growth cycle that modulates between infectious particles termed elementary bodies (EB) and non-infectious metabolical active particles termed reticulate bodies (RB). In the presence of IFN-gamma chlamydiae produce persistent infections in vitro, a host-parasite interaction that is believed to mediate in vivo chronic inflammatory disease. The genes that control the biphasic developmental cycle and IFN-gamma mediated persistent infection are unknown. We have used DNA microarray for transcriptional profiling chlamydial gene expression both during the natural infection growth cycle and during persistence, and reactivation from persistence. This approach has led to the identification of a small subset of genes that control the primary (immediate-early genes) and secondary (late genes) differentiation stages of the cycle. Immediate-early gene products initiate bacterial metabolism and potentially modify the bacterial phagosome to escape fusion with lysosomes. One immediate early gene (CT147) is of the human early endosomal antigen-1 that is localized to the chlamydial phagosome; suggesting a functional role for CT147 in establishing the parasitophorous vacuole in a non-fusogenic pathway. Late gene products terminate bacterial cell division and constitute structural components and remodeling activities involved in the formation of the highly disulfide cross-linked outer-membrane complex that functions in attachment and invasion of new host cells. Many of the genes expressed during the immediate-early and late differentiation stages are chlamydia-specific and have evolutionary origins in eukaryotic lineages. Genes involved in tryptophan utilization, DNA repair and recombination, phospholipid utilization, protein translation and general stress were up-regulated during persistence. Down-regulated genes during persistent growth were chlamydial late genes, and genes involved in proteolysis, peptide transport, and cell division. Persistence was characterized by altered but active biosynthetic processes with continued replication of the chromosome. Upon removal of IFN-gamma chlamydiae rapidly re-entered the normal developmental cycle and reversed transcriptional changes associated with cytokine treatment. The coordinated transcriptional response to IFN-gamma implies a chlamydial response stimulon has evolved to control the transition between acute and persistent growth of the pathogen. In contrast to the paradigm of persistence as a general stress response, our findings suggest persistence is an alternative life cycle employed by chlamydiae to avoid host inflammatory responses In summary, our findings identify new early and late genes that have important functions in modifying the host response to infection and in the remodeling of the chlamydial cell wall and outer membrane in transition form RB to EB. Moreover, transcriptome analysis of persistent infection has uncovered a chlamydial response stimulon that explains how chlamydiae persistent in cells and how they can become reactivated form persistence. These findings have considerable potential for the development of new and novel anti-chlamydial infectives.

沙眼衣原体是可预防失明的主要原因，也是性传播疾病的主要原因。衣原体是专性细胞内细菌，其特点是其独特的复杂双相生长周期，在称为初级体（EB）的感染性颗粒和称为网状体（RB）的非感染性代谢活性颗粒之间进行调节。在ifn存在的情况下，γ衣原体在体外产生持续感染，这种宿主-寄生虫相互作用被认为介导体内慢性炎症性疾病。控制双期发育周期和ifn - γ介导的持续感染的基因是未知的。