Distinct gene programs underpinning `disease tolerance` and `resistance` in influenza virus infection

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. Here we exploited interindividual variation in the host to identify central gene programs that act during the infection defense response. We developed and validated the model using transcriptomics and phenotypic data during in vivo influenza A virus (IAV) infection of 33 genetically diverse mouse strains that differ in their capacity to resist and tolerate disease, and by integrating high-throughput data of multiple isolated human cell types. The analysis demonstrated one transcriptional program that is associated with the strategy of disease tolerance and another program that is associated with the resistance strategy. In accordance, we refer to these programs as `disease tolerance` and `resistance` programs, respectively. Systematic analysis of human data across various healthy and inflammatory conditions indicated that the two programs are shared across multiple cell types – including non-immune, innate, and adaptive immune cells. We identified Arhgdia as a regulator of the disease-tolerance program during the host response to IAV infection. In vitro, changes in Arhgdia levels (by overexpression or knockout experiments) affected the IAV RNA levels in infected mouse lung epithelial cells and the death of these cells. Overall, our approach provides a paradigm for systematically studying disease-tolerance and resistance states.