LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2

Recent evidence indicates that tissue-resident innate immune memory and trained innate immunity (TII) can be induced centrally in myeloid cells within the bone marrow and locally in tissue-resident macrophages in respiratory mucosal tissues. However, it remains unclear whether acute exposure to airborne microbial components like lipopolysaccharide (LPS) induces lasting innate immune memory in airway macrophages and TII capable of protection against heterologous pathogens. Using a murine model, we demonstrate that acute LPS exposure leads to dynamic changes in the immune phenotype of airway macrophages that persist long after the acute inflammatory response has subsided. The original airway-resident alveolar macrophage pool remains stable in size despite these changes and the earlier transient acute inflammatory responses, including monocytic recruitment in the lung. We further demonstrate that the induction of innate immune memory in airway macrophages is accompanied by TII capable of robust protection against acute pneumococcal infection, whereas it provides minimal protection against acute SARS-CoV-2 infection.