Sequencing data of CLP mice

Secondary infection in septic patients triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality rate. Trained immunity boosts a potent and nonspecific response to the secondary challenge, and has been considered beneficial for the host to defend against secondary infection. Here, using a murine model of polymicrobial infection, we found that the primary infection reprogramed granulocytes to boost enhanced inflammatory responses in respond to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented capacity of phagocytosis. However, these reprogramed granulocytes exhibited 'non-classic' characteristics of innate immune memory. Single cell transcriptomic and epigenetic data revealed that two mechanisms are independently involved in innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis, and epigenetic reprogramming leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of trained granulocytes on anti-infection immunity might provide a new strategy to fight secondary infections during sepsis.