Shigella Induces Pro-Inflammatory Macrophages that Cooperate with Neutrophils to Protect from Secondary Infection

Abstract

Shigella is an important human pathogen for which there is no effective vaccine. Although decades of seminal work have shown that pathogenicity of Shigella relies on induction of inflammatory cell death in macrophages, the in vivo role of macrophages in controlling Shigella infection has been poorly understood. Here, we use a zebrafish model of innate immune training to investigate the antibacterial role of macrophages following a non-lethal infection by Shigella. We demonstrate that Shigella-induced neutrophil training does not require macrophages. Strikingly, macrophages are crucial for survival of zebrafish larvae during secondary Shigella infection. We show that following Shigella training, macrophages have altered their epigenome and shift towards a pro-inflammatory state characterised by increased tumour necrosis factor-alpha (TNF-⍺) expression. This shift is associated with increased antibacterial reactive oxygen species (ROS) production and enhanced survival. We conclude that Shigella-trained pro-inflammatory macrophages work alongside epigenetically reprogrammed neutrophils to protect against secondary infections.

Note:
Funding Information: Funding: D.B. was funded by the DFG Walter Benjamin Programme (BR 6637/1-1). Research in the SM laboratory is supported by a Wellcome Trust Senior Research Fellowship (206444/Z/17/Z), European Research Council Consolidator Grant (772853 - ENTRAPMENT), and Wellcome Discovery Award (226644/Z/22/Z).

Declaration of Interests: The authors declare no competing interests.

Keywords: Shigella, Zebrafish, infection biology, Macrophages, Neutrophils, trained immunity