Summary: A new, comprehensive open-access database showing gene activity in mice across ten disease models offers a complete view of immune responses and could substantially reduce the need for animal experiments worldwide.

Source: Francis Crick Institute

Comprehensive Mouse Gene Expression Resource Reveals Immune Responses Across Diseases

Scientists at the Francis Crick Institute have produced a large, searchable resource that maps the activity of more than 45,000 mouse genes in blood and, for six lung-related diseases, in lung tissue as well. Published in Nature Communications and made available through an online application, the dataset provides a detailed picture of how the immune system reacts to a diverse set of pathogens and allergens.

This resource lets researchers query the expression of any mouse gene across a wide range of infection and inflammation models without running their own animal experiments. By replacing many single-purpose studies, the database has the potential to dramatically reduce the number of mice used in research around the world.

The project was led by Crick group leader Anne O’Garra and coordinated by Christine Graham, with contributions from numerous collaborators in the UK and the United States. The team used next-generation RNA sequencing (RNA-seq) to measure transcriptional activity—RNA levels provide a direct readout of how actively each gene is being expressed following infection or allergen exposure.

Organizing Thousands of Genes into Biological Modules

Gene activity involves thousands of genes during any immune response. To make these data interpretable, Akul Singhania, a bioinformatics postdoctoral researcher in the group, applied advanced computational methods to cluster genes into co-regulated modules. Each module groups genes that behave similarly and often share biological functions. For example, among 38 lung modules identified, one module is specific to allergic responses and contains over 100 genes, while another module linked to T cell activity contains more than 200 genes.

By sequencing both lung tissue and blood from the same models, the team could compare local tissue responses with systemic signals in the blood. This comparison is important because lung tissue is rarely accessible in human patients, so understanding which lung signatures are mirrored in blood helps interpret clinical data and identify blood-based biomarkers.

A Panoply of Pathogens and Models

The searchable app lets researchers examine gene activity in lungs and blood from mice exposed to a wide set of pathogens and an allergen: the parasite Toxoplasma gondii, influenza virus, respiratory syncytial virus (RSV), the bacterium Burkholderia pseudomallei (both acute and chronic forms), the fungus Candida albicans, and the common allergen house dust mite. The dataset also includes blood profiles from mice infected with Listeria, murine cytomegalovirus, and the malaria parasite Plasmodium chabaudi chabaudi.

Analyses across these models revealed a spectrum of immune responses in the lung. Distinct modules were dominated by genes associated with Type I interferons, Type II interferon (IFN-γ), IL-17-driven neutrophil responses, or allergy-associated programs. Type I interferons tend to be produced during viral infection, while IFN-γ activates phagocytes to kill intracellular pathogens; IL-17 attracts neutrophils and drives early inflammation. The team found that Type I and IFN-γ–linked signatures present in lung tissue were often detectable in blood as well, whereas IL-17 and allergy-associated lung signatures were less reliably reflected in blood.

Unexpectedly, strong Type I interferon signatures were seen not only in viral infections but also in mice infected with the parasite Toxoplasma gondii and, to a lesser extent, the bacterium Burkholderia pseudomallei. These observations challenge the assumption that Type I interferon signatures exclusively indicate viral infection and echo earlier findings in tuberculosis.

Functional experiments confirmed the importance of interferon pathways in protecting against Toxoplasma: mice lacking functional Type I or Type II interferon signaling were less able to control infection. Both interferon pathways contribute to regulation of neutrophil numbers in blood—overabundant neutrophils can damage host tissues—highlighting the complex interplay between interferon signaling, granulocyte responses, protection, and pathology.

From Setback to Opportunity: Transitioning Technologies Saved the Project

The project began in 2009 using microarray technology to profile gene expression, and by 2015 the study was nearly complete. When the microarray reagents were discontinued by the manufacturer, the team faced the prospect of halted progress. Fortunately, RNA-seq had matured into a superior method for measuring transcription, and after negotiations the group received RNA-seq reagents and data storage support to reprocess their frozen samples.

Christine Graham re-extracted RNA from the stored tissue and blood samples and completed the RNA sequencing work in 2018 without using additional animals. The resulting raw data were large and complex; Akul Singhania then applied bioinformatics workflows to organize millions of data points into biologically meaningful modules and built the app that makes the data accessible to the global research community.

“Ten years since the project began, we now have an open-access resource of gene expression that anyone in the world can use to look up their favourite genes and also see whether they are regulated by Type I or Type II interferon signalling,” says Anne O’Garra. The dataset offers a powerful comparative framework for exploring transcriptional signatures that contribute to protection or pathogenesis in many diseases.

Source: Francis Crick Institute

Media contact: Harry Dayantis, Francis Crick Institute

Original research article: “Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases.” Akul Singhania, Christine M. Graham, Leona Gabryšová, Lúcia Moreira-Teixeira, Evangelos Stavropoulos, Jonathan M. Pitt, Probir Chakravarty, Annika Warnatsch, William J. Branchett, Laura Conejero, Jing-Wen Lin, Sophia Davidson, Mark S. Wilson, Gregory Bancroft, Jean Langhorne, Eva Frickel, Abdul K. Sesay, Simon L. Priestnall, Eleanor Herbert, Marianna Ioannou, Qian Wang, Ian R. Humphreys, Jonathan Dodd, Peter J. M. Openshaw, Katrin D. Mayer-Barber, Dragana Jankovic, Alan Sher, Clare M. Lloyd, Nicole Baldwin, Damien Chaussabel, Venizelos Papayannopoulos, Andreas Wack, Jacques F. Banchereau, Virginia M. Pascual & Anne O’Garra. Published in Nature Communications. DOI: 10.1038/s41467-019-10601-6.

Key takeaways:

• An open-access RNA-seq resource maps expression of over 45,000 mouse genes across ten disease models, in blood and, where relevant, lung tissue.
• Co-regulated gene modules reveal distinct immune programs—Type I and II interferon, IL-17/neutrophil, and allergy responses—many of which are conserved between lung and blood.
• The dataset enables researchers to query gene behavior across multiple infections and allergic models without performing new animal experiments, potentially reducing animal use.
• Interferon signaling pathways play a key role in controlling infection and inflammatory cell responses, with implications for understanding protection and pathology.