Historical contingency is revealed by trade-offs upon sequential adaptation to different infection routes

Past adaptation can shape how populations respond to subsequent selection. Because host-pathogen interactions vary widely in their ecological and physiological context, they provide a powerful system for testing the role of historical contingency in adaptation. Here, we evolved replicate populations of Drosophila melanogaster, previously adapted to systemic infection with Pseudomonas entomophila, under oral exposure to the same pathogen. Both evolutionary histories evolved increased survival under oral infection, but previous systemic adaptation altered the trajectory of this response in a sex-dependent manner. Females with a history of systemic selection began with lower oral-infection survival, yet adapted more rapidly than controls, whereas males showed weaker history-dependent differences. These contrasting trajectories could not be attributed simply to an overall loss of standing genetic variation in the founder populations. Adaptation to oral infection also incurred a trade-off, reducing survival under systemic infection, whereas the fecundity cost of infection did not differ between evolutionary histories. Finally, sex- and generation-specific changes in bacterial clearance revealed that adaptation to oral infection involved distinct mechanistic responses alongside shared genetic components. Together, our results show that past selection shapes both the tempo and mechanism of adaptation, revealing that responses to different infection ecologies are built on partially shared, but also route-specific, genetic architectures.