Comprehensive characterisation of transcriptional activity during influenza A virus infection reveals biases in cap-snatching of host RNA sequences

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J Virol. 2020 Mar 11. pii: JVI.01720-19. doi: 10.1128/JVI.01720-19. [Epub ahead of print] Comprehensive characterisation of transcriptional activity during influenza A virus infection reveals biases in cap-snatching of host RNA sequences.

Clohisey S^1,2, Parkinson N^1,2, Wang B^1,2, Bertin N³, Wise H^2,4, Tomoiu A^1,2; FANTOM5 Consortium, Summers KM⁵, Hendry RW¹, Carninci P⁶, Forrest ARR⁷, Hayashizaki Y⁶, Digard P², Hume DA⁸, Baillie JK⁹.
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Abstract

Macrophages in the lung detect and respond to influenza A virus (IAV), determining the nature of the immune response. Using terminal depth 5'-RNA sequencing (CAGE) we quantified transcriptional activity of both host and pathogen over a 24-hour timecourse of IAV infection in primary human monocyte-derived macrophages (MDM). This method allowed us to observe heterogenous host sequences incorporated into IAV mRNA, "snatched" 5' RNA caps, and corresponding RNA sequences from host RNAs. In order to determine whether cap-snatching is random or exhibits a bias, we systematically compared host sequences incorporated into viral mRNA ("snatched") against a complete survey of all background host RNA in the same cells, at the same time. Using a computational strategy designed to eliminate sources of bias due to read length, sequencing depth, multi-mapping, we were able to quantify over-representation of host RNA features among the sequences that were snatched by IAV. We demonstrate biased snatching of numerous host RNAs, particularly snRNAs, and avoidance of host transcripts encoding host ribosomal proteins, which are required by IAV for replication. We then used a systems approach to describe the transcriptional landscape of the host response to IAV, observing many new features, including a failure of IAV-treated MDMs to induce feedback inhibitors of inflammation, seen in response to other treatments.ImportanceInfection with influenza A virus (IAV) infection is responsible for an estimated 500,000 deaths and up to 5 million cases of severe respiratory illness each year. In this study we looked at human primary immune cells, macrophages, infected with influenza A. Our method allows us to look at both the host and the virus in parallel. We used this data to explore a process known as 'cap-snatching', where influenza A snatches a short nucleotide sequence from capped host RNA. This process was believed to be random. We demonstrate biased snatching of numerous host RNAs, including those associated with snRNA transcription, and avoidance of host transcripts encoding host ribosomal proteins, which are required by IAV for replication. We then describe the transcriptional landscape of the host response to IAV, observing new features, including a failure of IAV-treated MDMs to induce feedback inhibitors of inflammation, seen in response to other treatments.
Copyright ? 2020 Clohisey et al.


PMID: 32161175 DOI: 10.1128/JVI.01720-19
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