Host-associated niche metabolism controls enteric infection through fine-tuning the regulation of type 3 secretion

Abstract

Niche-adaptation of a bacterial pathogen hinges on the ability to recognize the complexity of signals from the environment and integrate that information with the regulation of genes critical for infection. Here we report the transcriptome of the attaching and effacing pathogen Citrobacter rodentium during infection of its natural murine host. Pathogen gene expression in vivo was heavily biased towards the virulence factor repertoire and was found to be co-ordinated uniquely in response to the host. Concordantly, we identified the host-specific induction of a metabolic pathway that overlapped with the regulation of virulence. The essential type 3 secretion system and an associated suite of distinct effectors were found to be modulated co-ordinately through a unique mechanism involving metabolism of microbiota-derived 1,2-propanediol, which dictated the ability to colonize the host effectively. This study provides novel insights into how host-specific metabolic adaptation acts as a cue to fine-tune virulence.

To B12 or not to B12: Five questions on the role of cobalamin in host-microbial interactions

“…In an analogous manner, cobalamin is required for enzymatic activity of propanediol dehydratase, which breaks down 1,2-propanediol, a metabolite that enhances Salmonella growth [20]. Additionally, cobalamin-dependent degradation of 1,2-propanediol releases breakdown product propionate, which promotes Citrobacter rodentium virulence during infection of the mammalian gastrointestinal tract [21] ( C . rodentium is a murine pathogen frequently used to model EHEC and enteropathogenic E .…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…216 Similarly, microbiome-derived 1,2-propanediol strengthens virulence factor expression in pathogens, supporting the intestinal colonization and expansion of pathogens such as C. rodentium. 217 Additional metabolite-mediated modulation of host metabolism Imidazole propionate, produced by type 2 diabetes-associated bacteria as a metabolite of histidine, is heightened in type 2 diabetes and impairs glucose tolerance and insulin signaling, a process achieved by inhibiting insulin receptor substrate (IRS) in a p38g/p62/mTORC1-dependent manner. 218 In a similar vein, the gut microbiome that harbors tyrosine phenol-lyase can catabolize dietary tyrosine into the precursor phenyl sulfate.…”

Advances and Challenges in Studying Type III Secretion Effectors of Attaching and Effacing Pathogens

“…Key to revealing novel and physiological phenotypes is the selection of an appropriate mouse strain, or knock-out mice (Simmons et al, 2002 ; Zheng et al, 2008 ; Carson et al, 2019 ). To highlight some examples, the mouse model has delineated Tir, NleA and NleB as essential effectors for efficient colonization (Deng et al, 2003 ; Mundy et al, 2004 ; Kelly et al, 2006 ), demonstrated the impact of individual effectors deletions on host physiology, such as EspO and EspS impacting CCH (Berger et al, 2018 ; Connolly et al, 2018 ), and substantiated in vitro data indicating Map impacts colonic oxygen availability through mitochondrial disruption (Berger et al, 2017 ). Recently, mouse-specific differences in infection signatures have been identified through RNAseq and proteomics (Kang et al, 2018 ; Carson et al, 2019 ); it remains to be seen whether these differences are fine-tuned by the synergistic action of the effectors.…”