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

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.

项目概要 微孢子虫是广泛分布、孢子传播的食源性/水源性病原体 人类的多种疾病，包括腹泻、支气管炎和脑炎。 机会性真菌病原体主要影响免疫功能低下的个体， 成为感染人类 HIV 患者的重要病原体。 来自脑炎原虫属的念珠菌可以通过内吞作用感染，如白色念珠菌，但这 通过内吞作用感染的病原体可以从中受益匪浅。 附着于宿主细胞和许多真菌物种，包括酵母编码细胞蛋白 其亚端粒的粘附特性也起着至关重要的作用。 通过编码多种病毒来开发针对宿主防御的致病对策 毒力因子和抗原变异体的副本，这是一种提供缓冲的意外情况 对抗有害突变和新因子产生的各种机会 不幸的是，我们不知道什么是通过重组来重组小构建块。 在人类感染性脑炎原虫的亚端粒区域中编码的基因是缺乏的，但即使在 测序的染色体核心，大约一半的预测蛋白质无法分配 任何假定的函数，由于它们的序列分歧程度很高，因此我们不知道 他们一半的蛋白质组是做什么的，这种知识的缺乏极大地限制了我们对其作用的理解。 这些病原体可以感染我们，例如，哪些脑炎寄生虫蛋白（如果有的话）可以感染我们 我们之前已经表明，具体触发宿主的内吞摄取是未知的。 Encephalitozoon spp. 的近亲 Ordospora colligata 微孢子虫 从它的宿主那里获得了一个脓毒蛋白，它可以充当这样的触发器，我帮助 脑炎原虫基因组编码一种或多种可以发挥这一作用的蛋白质。此外， 尽管它作为真核生物中的调控表达开关的重要性以及在 通过评估相应遗传位点的功能，微孢子虫甲基化组具有 在此，我建议找出许多尚待研究的毒力因素。 通过确定其完整，在感染人类的​​脑炎原虫中发现。 通过使用新颖的计算机改进功能预测，从端粒到端粒的序列 方法，并通过对它们的甲基化组进行测序，从实践的角度了解。 微孢子虫的甲基化状态不仅有助于更好地了解微孢子虫的功能 相应的基因座，而且还通过促进基于测序的感染诊断提供极大帮助 选择/开发适当的 DNA 富集试剂盒。

项目成果

Comparative genomics of microsporidian genomes reveals a minimal non-coding RNA set and new insights for transcription in minimal eukaryotic genomes.

• DOI: 10.1093/dnares/dsx002
• 发表时间: 2017-06-01
• 期刊: DNA research : an international journal for rapid publication of reports on genes and genomes
• 作者: Belkorchia A;Pombert JF;Polonais V;Parisot N;Delbac F;Brugère JF;Peyret P;Gaspin C;Peyretaillade E
• 通讯作者: Peyretaillade E

Telomere-to-Telomere genome assemblies of human-infecting Encephalitozoon species.

• DOI: 10.1186/s12864-023-09331-3
• 发表时间: 2023-05-04
• 期刊: BMC genomics
• 影响因子: 4.4

The Rad9-Rad1-Hus1 DNA Repair Clamp is Found in Microsporidia.

• DOI: 10.1093/gbe/evac053
• 发表时间: 2022-04-10
• 期刊: GENOME BIOLOGY AND EVOLUTION
• 影响因子: 3.3
• 作者: Dos Santos, Anne Caroline Mascarenhas;Julian, Alexander Thomas;Pombert, Jean-Francois
• 通讯作者: Pombert, Jean-Francois