SRA

The immune protection against invading pathogens is governed by pathogen elimination ('resistance') and by limitation of tissue damage that results from host-pathogen interactions ('tolerance'). However, distinct molecular states of resistance and tolerance remain obscure. Here, we collected longitudinal lung transcriptomes and clinical phenotypes of disease severity during influenza A virus (IAV) infection across 39 genetically-distinct mouse strains (32 strains of time series data and additional 7 strains with selected time points). Using transcriptional diversity in this data, we uncovered two key programs that together describe the cellular states for resistance and tolerance. The identified programs offer an unprecedented comprehensive view on shared and distinct roles of resistance and tolerance for the regulation of immune defense – for instance, we identified an antagonistic regulation of resistance and tolerance on protein production. Importantly, the framework reveals that both inflammatory states and the healthy steady state are remarkably diverse in resistance and tolerance levels, with implications on disease severity: a baseline state (before infection) of high tolerance and low resistance results in increased severity of IAV infection. Overall, our work provides a framework for the study of resistance and tolerance that could aid in clinical diagnosis and disease management. Overall design: To characterize the host defense, we investigated longitudinal data during IAV infection across genetically distinct mouse strains. We recorded lung transcriptomes of mouse strains of the collaborative cross (CC) cohort, both in steady state (before infection) and at five time points during the course of IAV infection (3h to 96h p.i.).