In form for a swarm: programmable neutrophil swarming impacts infection outcome

Migrating cells often pattern the distribution of chemoattractants to support their accumulation in target tissues. Neutrophil swarming represents a prominent example of such self-organisation. During this process, neutrophils engage in coordinated autocrine/paracrine chemoattractant signalling that drives rapid clustering at sites of injury or infection. Whether neutrophil swarming can be regeared to influence immune outcomes is unclear. Here, we show that neutrophil swarming is subject to reprogramming after microbial experience and amenable to targeted genetic engineering with measurable effects on infection outcome. We established a model of bacterial wound infection in zebrafish, focusing on P. aeruginosa, an important opportunistic pathogen. We demonstrate that zebrafish larvae exposed to prior microbial experience (with non-pathogenic E. coli) are more resistant to subsequent wound infection by P. aeruginosa, in comparison to naive animals. Through live imaging and chemical perturbations, we show that these training effects are in part attributed to changes in neutrophil swarming and associated gene expression. Finally, we demonstrate that genetic enhancement of 5-lipoxygenase in neutrophils is sufficient to maximise neutrophil swarming and improve infection outcome. Together, these data suggest new routes for reprogramming neutrophil accumulation in tissues, via manipulating their ability to shape chemoattractant landscapes.