Enhanced host protection and survival to Listeria monocytogenes infection after small molecule innate training

Abstract

Abstract Homeostatic training of innate immunity can improve protection against later infections. Our lab recently reported on small molecules that induce trained immunity in vitro. Here, we aim to show the protective potential of flunisolide (FN) using live infection model. We hypothesized FN training will alter hematopoiesis and innate functionality to improve outcome to L. monocytogenes. At homeostasis, FN training skewed towards GMP and MEP lineages and away from CLP lineage. To confirm FN-induced protection, mice were infected i.n. At d3 post-infection, FN mice showed lower pathogen burden in spleen, blood, and lung. Notably, systemic burden was lower in FN mice at d2 and d3. This may be due to improved immune functionality that led to faster clearance. To test this, phagocytosis and ROS levels at d3 were measured but no significant changes were seen. Further studies on lung immune functionality and earlier timepoints may show what hinders pathogen dissemination. BM at d7 after infection showed higher percentage of Lin+ in control and Lin- cells in FN mice. This suggests BM was recovering to homeostasis in FN mice, while inflammation control was active in control. Also, BM of FN mice had significantly higher percentage of CLP, suggesting earlier onset of adaptive immune response. Furthermore, FN mice showed improved survival up to d7. We showed FN can induce innate training, altering BM landscape at homeostasis and after infection, with improved response to L. monocytogenes.