Genomics of Virulence in Human-infecting Encephalitozoon

人类感染性脑炎原虫的毒力基因组学

• 批准号: 9231829
• 负责人: Jean-Francois Pombert
• 金额: $ 36.33万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-05 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231829
• 关键词: Adhesions; Adhesives; Affect; Bronchitis; Buffers; Candida albicans; Categories; Cells; Chromosomes; Computer Simulation; DNA; Detection; Development; Diagnostic; Diarrhea; Encephalitis; Encephalitozoon; Encephalitozoon hellem; Endocytosis; Eukaryota; Food; Gene Family; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Goals; HIV; Horizontal Gene Transfer; Host Defense; Human; Immune response; Immunocompromised Host; Individual; Infection; Keratoconjunctivitis; Kinetics; Knowledge; Lead; Left; MDK gene; Methylation; Microsporidia; Microsporidium; Mutation; National Institute of Allergy and Infectious Disease; Nucleotides; Organism; Orthologous Gene; Pathogenicity; Patients; Play; Process; Property; Proteins; Proteome; Reproduction spores; Role; Scheme; Septata intestinalis; Site; Specificity; Structure; Testing; Variant; Virulence; Virulence Factors; Yeasts; base; fighting; foodborne; improved; markov model; methylation pattern; methylome; nanopore; novel; oxidation; pathogen; public health relevance; telomere; uptake; waterborne; Adhesions; Adhesives; Affect; Bronchitis; Buffers; Candida albicans; Categories; Cells; Chromosomes; Computer Simulation; DNA; Detection; Development; Diagnostic; Diarrhea; Encephalitis; Encephalitozoon; Encephalitozoon hellem; Endocytosis; Eukaryota; Food; Gene Family; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genomics; Goals; HIV; Horizontal Gene Transfer; Host Defense; Human; Immune response; Immunocompromised Host; Individual; Infection; Keratoconjunctivitis; Kinetics; Knowledge; Lead; Left; MDK gene; Methylation; Microsporidia; Microsporidium; Mutation; National Institute of Allergy and Infectious Disease; Nucleotides; Organism; Orthologous Gene; Pathogenicity; Patients; Play; Process; Property; Proteins; Proteome; Reproduction spores; Role; Scheme; Septata intestinalis; Site; Specificity; Structure; Testing; Variant; Virulence; Virulence Factors; Yeasts; base; fighting; foodborne; improved; markov model; methylation pattern; methylome; nanopore; novel; oxidation; pathogen; public health relevance; telomere; uptake; waterborne

PROJECT SUMMARY Microsporidia are widely-dispersed, spore-disseminated foodborne/waterborne pathogens causing diverse afflictions in humans including diarrhea, bronchitis and encephalitis. These opportunistic fungal pathogens, which affect primarily immunocompromised individuals, have emerged as important pathogens of HIV patients. Human-infecting NIAID Category B species from the genus Encephalitozoon can infect by endocytosis, à la Candida albicans, but this process is poorly understood. Pathogens that infect by endocytosis greatly benefit from attachment to host cells and many fungal species including yeast encode proteins with cell adhesive properties in their subtelomeres. Subtelomeres also play a crucial role in the development of pathogenic countermeasures against host defenses by encoding multiple copies of virulence factors and antigenic variants, a contingency that provides both a buffer against deleterious mutations and various opportunities for the genesis of new factors from the shuffling of small building blocks via recombination. Unfortunately, our knowledge of what is encoded in the subtelomeric regions of human-infecting Encephalitozoon is lacking but even in the sequenced chromosome cores, about half of the predicted proteins could not be assigned any putative function due to their high level of sequence divergence, such that we have no idea what half of their proteome does. This lack of knowledge greatly limits our understanding of how these pathogens can infect us and, for example, which Encephalitozoon protein(s), if any, can specifically trigger the endocytic uptake from their host is unknown. We have previously shown that the closest relative of Encephalitozoon spp., the microsporidium Ordospora colligata, has acquired a septin from its host that can act as such a trigger, and I hypothesize that the Encephalitozoon genomes encode one or more proteins that can perform this role. Furthermore, despite its importance as regulatory on/off expression switches in eukaryotes and usefulness in assessing the function of the corresponding genetic loci, the microsporidian methylome has never been investigated. Here I propose to identify many of the virulence factors that are left to be discovered in the human-infecting Encephalitozoon spp. by determining their complete sequence from telomere-to-telomere, by improving functional predictions using novel in silico approaches, and by sequencing their methylome. From a practical perspective, knowing the methylation state of microsporidia will not only lead to a better functional understanding of the corresponding loci but also greatly help sequencing-based infection diagnostics by facilitating the selection/development of appropriate DNA enrichment kits.

项目摘要 微孢子虫是宽分散的，孢子解散的食源性/水传播病原体 在包括腹泻，支气管炎和脑炎在内的人类中引起了潜水员的感情。这些 主要影响免疫功能低下的个体的机会主义真菌病原体具有 出现是艾滋病毒患者的重要病原体。人类感染的NIAID类别B物种 来自脑脑脑症的属可以通过内吞作用感染，但这是 过程知之甚少。被内吞作用感染的病原体受益于 附着在宿主细胞和许多真菌物种上，包括酵母与细胞编码蛋白质 其亚telosemeres中的粘合特性。子telomeres在 通过编码多个来开发针对宿主防御的病原体对策 病毒因子和抗原变体的副本，这是一种既有缓冲区的意外事件 反对有害突变和各种机会，从而使新因素的起源 通过重组来改组小构件。不幸的是，我们对什么是 缺乏在人类感染脑感染的脑海中编码的地方 测序的染色体核心，大约一半的预测蛋白无法分配 由于其高序列差异而引起的任何推定功能，因此我们不知道 他们一半的蛋白质组有什么作用。缺乏知识极大地限制了我们对如何的理解 这些病原体会感染我们，例如，脑蛋白（如果有）可以 特异性触发其宿主的内吞摄取是未知的。我们以前显示了 脑孢菌属的最接近的亲戚，or虫司虫的colligata 从其宿主那里获得了一个可以作为触发的septin，我假设 脑结构基因组编码可以执行此作用的一种或多种蛋白质。此外， 任务是在真核生物中的调节/关闭表达开关的重要性 评估相应遗传局部的功能，Microsporidian甲基甲基机的功能 从未被调查过。在这里，我建议确定许多剩下的病毒因素 可以在人类感染的脑感染属于。通过确定他们的完整 通过使用新颖的硅中改善功能预测来改善功能预测， 接近，并通过对其甲基化测序。从实际的角度来看 微孢子虫的甲基化状态不仅会导致更好地理解 相应的语言环境，也可以通过促进基于测序的感染诊断 选择/开发适当的DNA富集试剂盒。