Viral-induced alternative splicing of host genes promotes influenza replication

Matthew G Thompson,Beatriz Ma Fontoura,Prasanna Bhat,Max B Ferretti,Michael J Mallory,Mark Dittmar,Kristen W Lynch,Sara Cherry

doi:10.7554/elife.55500

Matthew G Thompson, Beatriz Ma Fontoura + Show 6 more

Open Access

https://doi.org/10.7554/elife.55500

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Abstract

Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here, we show that infection of human lung epithelial cells with influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. Although these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, in several cases, specific inhibition of the IAV-induced splicing pattern also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein required for efficient splicing of the IAV M transcript in nuclear speckles. Finally, we find an increase in hnRNP K in nuclear speckles upon IAV infection, which may alter accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

Highlights

Influenza A virus (IAV) is a ubiquitous and significant health threat, resulting in 290,000–650,000 deaths per year worldwide (WHO, 2019)
As a first step toward understanding the impact of IAV infection on the transcriptome, human epithelial A549 cells were infected with IAV A/WSN/33 at a multiplicity of infection of 2, to yield ~90% infection of cells (Condit, 2013), and total RNA was isolated at 0, 6, and 12 hr post infection (HPI)
We identify a program of host splicing that is regulated by IAV infection and show that many of these splicing changes occur within genes that promote IAV replication

Summary

Introduction

Influenza A virus (IAV) is a ubiquitous and significant health threat, resulting in 290,000–650,000 deaths per year worldwide (WHO, 2019). IAV infection results in large changes to the host gene expression landscape Our understanding of these changes has largely been shaped through studies using microarray technology, limiting analyses to the measurement of transcript abundance. A recent transcriptome-wide study identified transcript abundance changes and global changes in alternative splicing isoforms (Fabozzi et al, 2018). These observations are in agreement with a growing awareness that viral infection can alter gene expression and lead to altered splicing patterns

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