| Project Detail |
Both antiviral immunity and susceptibility to viral infections are remarkably variable. Factors such as older age, increased body mass index, and male sex can increase the risk of developing severe viral disease, yet the impact of these features on antiviral immunity, particularly the type I interferon system (IFN-I), is not understood. Here we propose to use a systems immunology approach to identify features that influence IFN-I responses and understand their impact on infection susceptibility. We will use datasets and samples from the Milieu Interieur (MI) cohort of 1000 donors consisting 500 males and 500 females aged 20-69 years old. Using Simoa digital ELISAs, we have quantified IFN-I (IFNa and IFNb) in the supernatants of whole blood from the 1000 donors that was stimulated ex vivo with 7 agonists that activate the IFN-I system. Preliminary analysis of these results shows interesting age and sex differences in the IFN-I response. We will integrate the IFN-I cytokine data with existing demographic, microbiome, immune cell phenotyping and plasma protein data from the cohort and determine their associations with IFN-I levels. To investigate sex differences in IFN-I we will quantify sex hormones in the plasma of the 1000 donors. We will perform RNA-sequencing on IFNa-stimulated whole blood on a subset (n=200) of the donors to investigate the factors that shape the response to IFNa itself. We will perform genome wide association studies of the IFN-I response in the cohort to identify variants that influence IFN-I production using SNP genotyping data from MI. To determine the impact of these features on IFN-I and influenza infectivity in vitro, we will develop an organ on chip model encompassing features that we find to be associated with IFN-I levels in MI. Results from this project will identify novel regulators of IFN-I and shed light on new strategies to boost the antiviral response to better protect against viral infection. |
