Bulk RNA sequencing of total lung cells from Atg14f/f and Atg14f/f-LysM-cre mice.

Here, we describe innate immune priming prior to infection that conferred resistance to respiratory pathogens. The lung innate immune priming for early response to infection occurred via functional reprogramming of innate immune cells independently of either the microbiome or adaptive immunity.

In normal animals, priming was suppressed by autophagy in alveolar macrophages, rendering animals susceptible to infection. Mice lacking autophagy in myeloid cells demonstrated swifter and more efficient innate immune clearance of Staphylococcus aureus infection while minimizing lung damage and inflammation. Enhancing the primed state of innate immunity by blocking autophagy also protected against influenza A virus.