sRNA centered signaling activates nitrate respiration and enhances Cronobacter sakazakii virulence in host environments

Cronobacter sakazakii is an important neonatal pathogen frequently associated with powdered infant formula. However, the mechanisms by which C. sakazakii adapts to the host environment and establishes systemic dissemination remain poorly understood. Here, we reveal a signal transduction pathway centered on a novel sRNA, CsrN, which facilitates C. sakazakii in utilizing nitrate respiration in response to oxygen-limited environments within the host, thereby enhancing its virulence in vivo. C. sakazakii infection triggers an inflammatory response, leading to the accumulation of host-derived nitrate, a key alternative electron acceptor. The expression of CsrN is induced under anaerobic conditions via the ArcAB two-component regulation system. CsrN subsequently enhances the expression of the narGHJI operon, which encodes a nitrate reductase complex. This promotes the colonization of C. sakazakii in the gastrointestinal tract and benefits its survival within macrophages, ultimately leading to increased systemic bacterial dissemination and virulence in the host. We show that administration of tungstate, a specific inhibitor of nitrate respiration, significantly attenuates C. sakazakii virulence in animal experiments. This work provides novel insights into the survival and pathogenicity mechanisms employed by C. sakazakii in host environments and suggests nitrate respiration as a potential therapeutic target for combating C. sakazakii infections.