Infection-experienced HSPCs protect against infections by generating neutrophils with enhanced bactericidal activity

Abstract

Hematopoietic stem and progenitor cells (HSPCs) respond to infection by proliferating and generating in-demand neutrophils through a process called emergency granulopoiesis (EG). Recently, infection-induced changes in HPSCs have also been shown to underpin the longevity of trained immunity, where they generate innate immune cells with enhanced responses to subsequent microbial threats. Using larval zebrafish to live image neutrophils and HSPCs we show that infection-experienced HSPCs generate neutrophils with enhanced bactericidal functions. Transcriptomic analysis of EG neutrophils uncovered a previously unknown function for mitochondrial reactive oxygen species in elevating neutrophil bactericidal activity. We also reveal that driving expression of zebrafish C/EBPbeta within infection-naive HSPCs is sufficient to generate neutrophils with similarly enhanced bactericidal capacity. Our work suggests that this demand-adapted source of neutrophils contributes to trained immunity by providing enhanced protection towards subsequent infections. Manipulating demand-driven granulopoiesis may provide a therapeutic strategy to boost neutrophil function and treat infectious disease.

The emerging role for neutrophil mitochondrial metabolism in lung inflammation

“…In a zebrafish larvae model of Salmonella enterica infection, neutrophils exhibit trained immunity that protects from subsequent infection. Neutrophils derived from infection-experienced hematopoietic stem and progenitor cells have increased mitochondrial mass, have increased mitochondrial ROS production, and demonstrate enhanced bacterial killing that is mitochondrial ROS dependent [77] . Through the generation of ROS, mitochondrial metabolism contributes directly to fundamental neutrophil effector functions.…”