Age-dependent Susceptibility To Virus Infection Is Governed by Host Genetics

Abstract

Abstract While improved sanitation and medical care have reduced the burden of infectious disease, it remains the 4th leading cause of death in the elderly. Coupled with the expansion of the aged population over the next two decades, understanding the interplay between infection and the senescent host is critical. Both the microbiome and host genetics have been predicted to play critical roles in aging immunity. In this work, we explore the role of each in age-dependent susceptibility to virus infection. Severe acute respiratory syndrome coronavirus (SARS-CoV), the first outbreak virus of the 21st century, produces increased disease in aged patients as compared to the young. Importantly, age-dependent susceptibility is observed in mouse models of SARS-CoV infection. Our results indicate that despite microbiome variation between young and aged animals, limiting these differences had only a marginal effect on disease in the aged following infection. In contrast, age-dependent susceptibility was not fully conserved across genetically diverse Collaborative Cross (CC) mice. We found that while the majority of CC lines maintained increased disease as they aged, several lines showed no distinction between young and aged animals. In one CC line, we found that aged mice were more resistant to SARS-CoV infection than their younger equivalent. Notably, age-dependent susceptibility was not simply associated with higher viral loads driving augmented disease. Instead, the results suggest that host factors including tissue and inflammation responses govern disease in the senescent host. Together, the work highlights the importance of genetic elements in driving age-dependent disease following infection.