A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease

Abstract

Making the most of “big data” is one of the core challenges of current biology. There is a large array of heterogeneous data sets of host gene responses to infection, but these data sets do not inform us about gene function and require specialized skill sets and training for their utilization. Here we describe an approach that combines and simplifies these data sets, distilling this information into a single list of genes commonly upregulated in response to infection with RSV as a model pathogen. Many of the genes on the list have unknown functions in RSV disease. We validated the gene list with new clinical, in vitro, and in vivo data. This approach allows the rapid selection of genes of interest for further, more-detailed studies, thus reducing time and costs. Furthermore, the approach is simple to use and widely applicable to a range of diseases.

Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus

“…Our data showing an antiviral role for IFI44 and IFI44L matches our previous study using a lentivirus screen (8) and a broader screen by another group using the same lentivirus panel (14). However, the data presented here is somewhat at odds with recently published studies investigating the impact of IFI44 (42) and IFI44L (43) on virus in vitro.…”

“…Our in vitro studies have some limitations, primarily the use of clonal cell lines to assay infection and proliferation. We note that transduction of polyclonal parental A549 cells with IFI44 is capable of restricting RSV infection similarly to the stably transduced cells, and that previous studies have observed similar impacts of IFI44 on proliferation (13, 18) or restriction of RSV (8). However, it is possible that clone-specific differences have some impact on either RSV infection or cell viability and these data should be interpreted with this limitation in mind.…”

“…We have previously identified a number of ISGs that are consistently upregulated in response to RSV (8), of which IFI44 and IFI44L featured prominently. We focussed on these two genes as relatively little was known of their phenotype.…”

“…Understanding how these genes reduce viral infection gives insight into the viral life cycle and may open up novel therapeutic routes. We have previously performed a bioinformatic screen of ISG expressed after RSV infection, which prioritised ISG of interest for further study (8).…”

A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus

“…Up-regulation of CLRs activates antiviral immune responses such as antigen processing and presentation, T cell activation and phagocytosis, suppressing viral dissemination within the host. Nevertheless, CLRs can be a double-edged sword as some viruses have evolved to use these receptors for viral entry into host cells, avoiding immune recognition, where kidnapping the host cell machinery they produce hundreds of new copies of themselves spreading their copies further into the host [54].…”