PAMPS and Innate Immune Memory

Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with ß-glucan, a fungus-derived Dectin-1 ligand, and monophosphoryl lipid A (MPLA), a bacteria-derived TNS4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, their recruitment to the site of infection, augmentation of microbial clearance and attenuation of cytokine production. Examination of macrophages ex vivo showed that metabolism, phagocytosis and respiratory burst were amplified by treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions and protein synthesis and suppressed pathways regulating cell division with MPLA more potently inducing global gene transcription. ß-glucan treatment minimally modified macrophage differential gene expression in response to LPS challenge compared to control whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response. These results show that b-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS. Overall design: Bone marrow-derived macrophages from WT C57BL/6 mice were treated with ß-glucan, monophosphoyl lipid A (MPLA), lipopolysaccaride (LPS), vehicle (DMSO or normal saline (NS)), or multiple treatments in sequence. We then performed gene expression profile analysis from 2-3 biological replicates per treatment at multiple timepoints. The effects on the transciptome were compared between groups. This data comes from 3 batches of RNA sequencing, and analysis of each batch was perfomed relative to its own vehicle controls. Samples 1-18 are a batch, as are samples 19-30, and 31-36.