PGLYRP4 Enhances <i>Shigella flexneri</i> Virulence by Promoting <i>virF</i> Transcription via the CpxA/R Two‐Component System

The human gastrointestinal tract provides a complex environment for bacterial pathogens, necessitating their adaptation to host defenses and microbiota. Shigella, a Gram-negative bacterium responsible for bacillary dysentery, has evolved sophisticated mechanisms to regulate its virulence in response to intestinal signals. This study focuses on the role of peptidoglycan recognition protein 4 (PGLYRP4), a component of the host's innate immune system, in modulating Shigella's virulence. We demonstrate that PGLYRP4, at sub-bactericidal concentrations, significantly induces the transcription of the virulence regulator virF, through the CpxA/R TCS activation, therefore enhancing Shigella's infectivity without compromising bacterial viability. Moreover, our findings suggest that Shigella has developed an increased capacity to respond to oxidative stress, including that induced by PGLYRP4, through the basal upregulation of genes involved in detoxifying reactive oxygen species. This adaptation likely helps the pathogen counteract the bactericidal effects of PGLYRP4. Based on the results of our experiments and the literature, we hypothesize that Shigella uses PGLYRP4, which is produced by stimulated enterocytes in response to cytokines released by pyroptotic macrophages, as a molecular cue to enhance its ability to invade enterocytes. This study contributes to improving our understanding of bacterial pathogens' adaptation strategies by showing that they can evolve to compete more effectively with their hosts by using factors of the hosts' arsenal.