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

系统生物学方法揭示了人类巨细胞病毒（HCMV）基因组中数百个翻译开放阅读框和数千个转录起始位点。以往的研究主要以成纤维细胞为模型系统。然而，有证据表明，HCMV基因表达在感染细胞类型之间存在很大差异。我们将揭示细胞类型特异性的HCMV转录组和翻译组，并阐明HCMV如何篡位细胞和病毒因子，使病毒基因表达适应不同细胞类型在裂解感染期间的不同代谢和免疫条件。我们将验证从瞬时rna的非生产性转录到稳定rna的生产性转录的转换定义了HCMV的细胞类型特异性和时间依赖性转录组，以及uORFs微调蛋白质翻译的假设。我们将进一步开发数学模型，整合表达数据和MHC-I配体定量数据，以研究基因表达动力学如何与细胞和病毒抗原的MHC-I肽呈递相关。我们将与研究小组的其他成员合作，利用我们的研究结果来确定和验证用于诊断、预防或治疗HCMV感染的新靶点。

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.