The Host Genetics of Age-Dependent Susceptibility

Abstract Both aging and host genetics play a critical role in susceptibility to viral infection. In our proposal, we use the Collaborative Cross (CC), a novel mouse genetic resource, to explore how host genetics impacts age dependent susceptibility to infection. Infection with Severe Acute Respiratory Syndrome coronavirus (SARS- CoV), the first outbreak virus of the 21st century, caused a range of respiratory infection with more serve disease observed in patients over the age of 50. Importantly, aging susceptibility is conserved in mouse models of SARS-CoV infection and increased disease is not due to higher viral load in older animals. The results indicate host responses drive differential disease in the aged. However, age-dependent susceptibility is not completely conserved across the genetically diverse CC populations. Screening eleven CC lines with SARS-CoV infection at 18 months old, we identified seven lines with more disease as they aged, three lines equivalent to their younger controls, and one line more resistant as it aged. Together, our preliminary results indicate that certain genetic elements contribute to age-dependent susceptibly to SARS-CoV infection. Building from this screen, we will generate an F2 cross using a CC line with age-dependent susceptibility and a CC line without; we will then challenge both young and aged F2 mice to further characterize genetic loci that contribute to SARS-CoV disease and to identify QTL specifically associated with aging and age-dependent disease. We anticipate that these novel genetic loci will provide a foundation for understanding the role of genetic diversity in SARS-CoV disease and aging processes. We expect the results to also to inform future treatment approaches for elderly patients.