Cell type-specific HCMV gene expression and its consequences for the MHC-I immunopeptidome

细胞类型特异性 HCMV 基因表达及其对 MHC-I 免疫肽组的影响

• 批准号: 421449004
• 负责人: Professor Dr. Lars Dölken
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/421449004?language=en
• 关键词: Cell; type; specific; HCMV; gene

Systems biology approaches uncovered hundreds of translated open reading frames and thousands of transcription initiation sites in the genome of human cytomegalovirus (HCMV). Previous studies focused on fibroblasts as model system. There is, however, evidence that HCMV gene expression differs substantially among infected cell types. We will uncover the cell type-specific HCMV transcriptome and translatome and will elucidate how HCMV usurps cellular and viral factors to adapt viral gene expression to the different metabolic and immunological conditions within different cell types during lytic infection. We will test the hypotheses that switches from non-productive transcription of transient RNAs to productive transcription of stable RNAs define the cell type-specific and time dependent transcriptome of HCMV and that uORFs fine-tune the translation of proteins. We will furthermore develop mathematical models to integrate expression data and quantitative MHC-I ligandome data to investigate how the kinetics of gene expression is related to MHC-I peptide presentation for both cellular and viral antigens. In collaboration with the other members of our RU we will use our findings to identify and validate novel targets for diagnostic, prophylactic or therapeutic approaches to combat HCMV infections.

系统生物学方法揭示了人巨细胞病毒（HCMV）基因组中数百个翻译的开放阅读框架和数千个转录起始位点。以前的研究主要集中在成纤维细胞作为模型系统。然而，有证据表明HCMV基因表达在感染的细胞类型中有很大差异。我们将揭示细胞类型特异性HCMV转录组和translatome，并将阐明HCMV如何篡夺细胞和病毒因子，以适应病毒基因表达的不同代谢和免疫条件下，在不同的细胞类型裂解感染。我们将测试从瞬时RNA的非生产性转录到稳定RNA的生产性转录的转换定义HCMV的细胞类型特异性和时间依赖性转录组以及uORF微调蛋白质翻译的假设。我们将进一步开发数学模型来整合表达数据和定量MHC-I配体组数据，以研究基因表达的动力学如何与细胞和病毒抗原的MHC-I肽呈递相关。通过与RU的其他成员合作，我们将利用我们的研究结果来确定和验证诊断，预防或治疗方法的新靶点，以对抗HCMV感染。