Lactation-induced granulopoiesis and pulmonary epithelial remodeling enhance maternal antiviral defense 2259314

Abstract Introduction During pregnancy, the maternal systemic immune system shifts toward tolerance to safeguard the semi-allogenic fetus. However, how the maternal immune system adapts during lactation, a critical yet poorly understood stage across barrier tissues, where infections are most likely to occur, remains poorly understood. Methods We employed a murine timed-pregnancy model, combined with flow cytometry, imaging, and transcriptomic profiling to examine lung epithelium-immune crosstalk across reproduction. We further investigate maternal susceptibility to common respiratory viral and bacterial infections. Results We identified neutrophils as a unique expanded population in the lungs of lactating dams, increasing up to 3-fold in number compared to non-lactating and pregnant controls. Lung neutrophil induction was specific to lactation, increasing in the bone marrow, followed by recruitment into the pulmonary vasculature. Transcriptomic analysis revealed that the lung epithelium upregulated numerous innate defense pathways, including sulfactant, mucus, antimicrobial peptide, and complement production, and neutrophil recruitment. Strikingly, during lactation, lung neutrophils displayed heightened antiviral signatures. As a result of immune and epithelial remodeling, lactating dams exhibited reduced viral burden and improved survival following respiratory viral infection. Conclusion Our work reveals that lactation induces distinct and previously unrecognized remodeling of the pulmonary immune and epithelial landscapes. Such adaptations enhance maternal defense against respiratory pathogens and may represent a strategy to compensate systemic immunosuppression and survive in a pathogen rich environment at such a critical stage in life, protecting both the mother and offspring. Ongoing work focuses on dissecting the contributions of microbiota and hormones, and examining the conservation of these adaptations in marmoset and sugar glider models. Funding Source Princeton University Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)