Regulation of the integrated stress response to viral infection by RNA modifications

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State primary research question and where appropriate the primary hypotheses being tested The hypothesis is that the m6A modifications have a role in the dynamic regulation of cellular and viral gene expression in the context of the integrated stress response and other antiviral pathways. The aim is to explore this hypothesis by generating human lung cell lines that are depleted in m6A writers, readers or erasers in combination with infection with influenza A virus or SARS-CoV-2. Importantly, these respiratory viruses have different replication strategies and interactions with the host cell. Viral replication in the context of modulating the m6A system and mutations in the viruses that sensitise them to the innate immune system will be analysed. The most robust phenotypes will be subjected to an unbiased (genome-wide) profiling of mRNA expression and translation with the outcomes functionally validated.