Age-Related Changes to the Immune System Exacerbate the Inflammatory Response to Pandemic H1N1 Infection

Age-induced dysregulation of the immune response is a major contributor to the morbidity and mortality related to influenza a virus infections. Experimental data have shown substantial changes to the activation and maintenance of the immune response will occur with age, but it remains unclear which of these many interrelated changes are most critical to controlling the survival of the host during infection. To ascertain which mechanisms are predominantly responsible for the increased morbidity in elderly hosts, we developed an ordinary differential equation model to simulate the immune response to pandemic H1N1 infection. We fit this model to experimental data measured in young and old macaques. We determined that the severity of the infection in the elderly hosts is caused by a dysregulation in the innate immune response. We also simulated CD8(+) T cell exhaustion, a common consequence of chronic and extensive infections. Our simulations indicate that while T cell exhaustion is possible in both age groups, its effects are more severe in the elderly population, as their dysregulated immune response cannot easily compensate for the exhausted T cells. Finally, we explore a therapeutic approach to reversing T cell exhaustion through an inflammatory stimulus. A controlled increase in inflammatory signals can lead to a higher chance of surviving the infection, but excess inflammation will likely lead to septic death. These results indicate that our model captures distinctions in the predominant mechanisms controlling the immune response in younger and older hosts and allows for simulations of clinically relevant therapeutic strategies post-infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11538-022-01045-z.