Developmental origin of sex differences in lung-resident immunity upon prenatal adversities

Background: Prenatal adversities can increase the risk and severity of lung diseases. Sex differences play a role in the pathogenesis of such diseases. Little is known about the impact of prenatal adversities on sex-differences in lung health. Aims: Here, we aimed to examine if and how prenatal stress affects the sexual dimorphism of respiratory infections with a strong female bias (Influenza A, IAV) through modulation of lung-resident immunity. Methods: Pregnant C57BL/6 mice were exposed to sound stress on gestational days 9.5, 11.5, 13.5, and 15.5. 8 weeks after birth, male and female offspring were infected with 10³ P.F.U. H1N1 IAV. Survival and weight loss were monitored and mice were sacrificed on day 3, 6 and 14 post infection (dpi) for viral load and immune response assessment. Results: Our findings confirm that the infection course, based on weight loss and mortality, is more severe in female offspring unexposed to prenatal stress, compared to non-stressed male offspring. Strikingly, a reduced morbidity and mortality was observed in prenatally stressed female offspring, compared to non-stressed females. In prenatally stressed females, we detected increased lung-infiltrating monocytes, tissue-resident dendritic cells and alveolar macrophages on 3 dpi, along with higher cortisol levels. On 14 dpi, lung inflammation was more efficiently resolved in prenatally stressed female mice compared to non-stressed females. Conclusions: Our data underpin that an adjustment to variable environments occurs specifically in female offspring upon stress challenge, referred to as phenotypic plasticity. The advantage is a reduced risk for influenza infection. Other trade-offs remain to be identified.