Heterotypic immune mice lose protection against influenza virus infection with senescence

Influenza causes significant morbidity and mortality in the elderly. To determine whether this could be due to loss of heterotypic immunity, young and aged BALB/c mice were made heterotypically immune by H3N2 influenza virus infection and then challenged, while anesthetized, with H1N1 virus. Viral clearance was delayed by 2 days in the aged mice. Naive and heterotypic immune mice were next challenged with H1N1 virus while awake. Under these conditions, initial infection was restricted to the nose in all animals. The virus spread to the lungs of the young and aged naive mice but not of heterotypic immune young mice. Heterotypic immunity of aged mice did not prevent spread of the virus to the lungs. The impaired recovery of aged mice correlated with lower antiinfluenza cytotoxic T lymphocyte (CTL) activity. Thus, a possible explanation for the increased severity of influenza in elderly humans is loss of CTL-mediated heterotypic immunity.