Pregnancy stages differentially impact maternal alveolar macrophages' function and immunity to SARS-CoV-2 infection

Pregnancy comes with complex immune adaptations to support the specific needs of each pregnancy stage. Infections during pregnancy pose an additional challenge in keeping the fine balance between protective and detrimental immune activation. Whether mucosal immunity adapts to different pregnancy stages is poorly understood. Through detailed profiling of lung immune cells, we discovered a selective expansion of tissue-resident alveolar macrophages (TR-AMs) during late gestation. Using scRNA-seq we identified TR-AMs as the functionally most altered pulmonary immune cells that exhibited an anti-inflammatory transcriptional state, reduced cellular interactions and diminished responsiveness to viral ligands. This gestation-stage-specific adaptation shaped the response to SARS-CoV-2 infection. While early-stage pregnant animals showed an enhanced anti-viral response and accelerated viral clearance, late-stage pregnancy infection mirrored the dampened immune state of TR-AMs and prevented exaggerated lung tissue damage. We postulate that pulmonary immune adaptations in pregnancy augment defenses to protect fetal development in early stages, yet preserve maternal fitness required for parturition at later stages.