Modeling childhood resistance to influenza mortality in mice (169.14)

Abstract

Abstract In the 1918 influenza pandemic, infected children between ages 5-14 had low mortality. To study the mechanisms for childhood resistance to disease mortality, we created a murine model of mortality difference from influenza (flu) in pre-pubertal (Pre-P) vs. post-pubertal (P) mice (onset is day 28). We compared mortality rates in C57BL/6 (Pre-P) and (P) mice infected with the same viral dose (1 HAU of A/PR/8/34). We also used gonad-intact and gonadectomized (Gx) mice that received hormone replacement to test the effect of sex steroids on morbidity and mortality during flu infection. Mortality was lower in Pre-P mice (22% for infections started on postnatal day 25 (P25), 16% at P26) when compared to P mice (71% at P28, n > 18, p<0.05). Data were similar for both sexes. In the sex steroid-ablated Gx mice, mortality was also lower (23 % vs. 64%, 28% vs. 50% for the castrated vs. sham-castrated, and ovariectomized (Ox) vs. sham-Ox mice, respectively). Gx female mice treated with estrogen (E) replacement (i.p. (E), 10ug/100ul) showed an increase in mortality (28% in Ova+vehicle (V) vs. 71%, 66% and 80% respectively, for the Ova+E, sham-Ova+V and sham-Ova+E mice, p=0.057). Histopathology showed severe lung injury with hyaline membranes in all E-intact, however, this pathology was absent in (V)-treated Gx mice. The model will be useful for further studies of how sex hormones, e.g. (E), and other host factors may contribute to mortality after influenza infection.