Functional characterisation of interferon stimulated genes in respiratory viral infection

Abstract

A key element of host antiviral defence is cell intrinsic immunity, driven by an array of interferon stimulated genes (ISGs), few of which have been properly characterised. However, the breadth of ISG antiviral mechanisms suggests this gene network can target nearly every stage of a viral life cycle. Respiratory syncytial virus (RSV) is responsible for a vast number of infections, primarily in infants. Intriguingly, most infants requiring hospitalisation with a severe RSV infection present with no known risk factor. It was hypothesised that ISGs induced by RSV infection represent potential genetic risk factors that could influence virus control and disease severity between individuals. The IFN-induced transmembrane (IFITM) family of ISGs are broadly antiviral and thought to target virus entry. The data presented here expand our understanding of IFITM1 function by demonstrating that antiviral activity is dependent upon plasma membrane localisation. The in vivo relevance of IFITM1 was also probed in a monogenic knockout mouse model, for the first time demonstrating that the loss of IFITM1 alone is sufficient to result in a loss of viral control and enhanced disease severity. Next, the role of IFN-induced protein 44 (IFI44) proteins was explored as these ISGs are especially poorly characterised and are highly induced by RSV infection. There are conflicting data on the antiviral activity of IFI44 and IFI44L during RSV infection. This study presents evidence that these genes are antiviral, impacting an early point of the viral life cycle associated with reduced polymerase activity. Finally, the loss of IFI44 in vivo was shown to result in increased RSV disease severity.