(880) Defining pulmonary immune responses in microbially experienced mice.

Introduction/Rationale: Mouse models are essential tools in research, yet their relevance to humans is limited by the artificial conditions under which they are raised. The contrast between humans’ constant exposure to diverse microbes and the highly controlled environments of animal models remains a major barrier to translational research. To bridge this gap, specific pathogen-free (SPF) mice can be converted into microbially experienced (ME) mice through exposure to various microorganisms. These mice more closely resemble an adult human-like immune system, though many aspects of the model are still unknown. While current ME studies have centered their attention on the adaptive immunity, emerging evidence suggests key alterations in the innate immune compartment of the ME model.

Methods: Here, we generated ME mice by sequential infections with model organisms for common human pathogens (Murine gammaherpesvirus 68, Murine hepatitis virus A59, Heligmosomoides polygyrus). We then examined their pulmonary immune environment and responses to respiratory infections.

Results: Our recent work revealed innate cell shifts in ME mice, including a decrease in alveolar macrophage, nerve- and airway-associated macrophage, and an increase in interstitial macrophage populations in comparison to SPF mice. During Influenza A virus infection, ME mice displayed heightened inflammatory signatures and greater immune cell infiltration in the lung tissue, while sustaining a reduction of macrophage and monocyte populations.

Conclusion: Together, these results demonstrate that microbial experience significantly reshapes innate immunity in the lungs, highlighting possible crucial cell components for modeling an adult human-like immune system in vivo. This model provides a valuable platform for better understanding host–pathogen interactions and may improve the translation of preclinical findings to human disease.