Childhood Resistance to Influenza Mortality: Analysis in a Mouse Model

Abstract

During the 1918 influenza pandemic, children experienced significantly lower mortality compared to adults, with the onset of puberty marking a transition to greater disease susceptibility. To explore the mechanisms that may underlie childhood resistance, we assessed mortality in prepubertal and pubertal (C57BL/6) mice infected with H1N1 influenza (A/PR/8/34). We found significantly decreased influenza mortality in prepubertal mice of both sexes (16%) when compared to pubertal mice (71%, p<0.05), and lung injury was more severe in pubertal mice with hyaline membrane deposition. Mice treated with a GnRH antagonist or subjected to gonadectomy to block the onset of puberty had improved survival when compared to control age-matched mice with normal puberty (p= 0.0054). In addition, gonadectomized mice lost their resistance to flu mortality after receiving estrogen hormone replacement (p=0.057). Transcriptome profiling of infected lungs supported a deleterious role for the pubertal-onset hormone estrogen, and also identified higher expression of IL-1beta in mice with the highest mortality. Estrogen receptor blockade with fulvestrant in male and female adult mice, even when given three days after infection, resulted in improved survival (p = 0.0055 and p =0.0062, respectively). Moreover, late but not early, IL-1beta neutralization given during the post-infection period was also protective (p=0.0018). These findings suggest that the surge of estrogen that occurs with puberty and unopposed IL-1beta during the later period of influenza infection may result in a perturbation of the immune response that results in poor outcomes during influenza infection. The data begin to explain the remarkable childhood resistance to mortality from severe infections exemplified in the 1918 influenza pandemic.