Influenza virus replicates intracellularly exploiting several pathways involved in the
regulation of host responses. The outcome and the severity of the infection are thus
strongly conditioned by multiple host factors, including age, sex, metabolic, and redox
conditions of the target cells. Hormones are also important determinants of host immune
responses to influenza and are recently proposed in the prophylaxis and treatment. This
study shows that female mice are less susceptible than males to mouse-adapted influenza
virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher
survival rate (+36%), milder clinical disease, and less weight loss. They also have milder
histopathological signs, especially free alveolar area is higher than that in males, even
if pro-inflammatory cytokine production shows slight differences between sexes; hormone
levels, moreover, do not vary significantly with infection in our model. Importantly,
viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose
50%) are lower in PR8-infected females. An analysis of the mechanisms contributing
to sex disparities observed during infection reveals that the female animals have higher
total antioxidant power in serum and their lungs are characterized by increase in (i) the
content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant
enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression
of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by
high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both
enzymes promoting viral replication. All these factors are critical for cell homeostasis and
susceptibility to infection. Reappraisal of the importance of the host cell redox state and
sex-related effects may be useful in the attempt to develop more tailored therapeutic
interventions in the fight against influenza
