l -Arginine sensing regulates virulence gene expression and disease progression in enteric pathogens

Abstract

Microbiota, host and dietary metabolites/signals compose the rich gut chemical environment, which profoundly impacts virulence of enteric pathogens. EnterohemorrhagicEscherichia coli(EHEC) engages a syringe-like machinery named type-III secretion system (T3SS) to inject effectors within host cells that lead to intestinal colonization and disease. We previously conducted a high-throughput screen to identify metabolic pathways that affect T3SS expression. Here we show that in the presence of arginine, the arginine sensor ArgR, identified through this screen, directly activates expression of the genes encoding the T3SS. Exogenously added arginine induces EHEC virulence gene expression in vitro. Congruently, a mutant deficient in arginine transport (ΔartP) had decreased virulence gene expression. ArgR also augments murine disease caused byCitrobacter rodentium, which is a murine pathogen extensively employed as a surrogate animal model for EHEC. The source of arginine sensed byC. rodentiumis not dietary. At the peak ofC. rodentiuminfection, increased arginine concentration in the colon correlated with down-regulation of the host SLC7A2 transporter. This increase in the concentration of colonic arginine promotes virulence gene expression inC. rodentium. Arginine is an important modulator of the host immune response to pathogens. Here we add that arginine also directly impacts bacterial virulence. These findings suggest that a delicate balance between host and pathogen responses to arginine occur during disease progression.

Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens

“…CR mutants unable to sense LEE-activating signals are attenuated. However, several of these mutants are not completely avirulent and unable to colonize the gut (Curtis et al, 2014;Moreira et al, 2016;Pifer ll et al, 2018;Menezes-Garcia et al, 2020). The DqseC can still colonize mice, albeit to a lesser degree than WT CR.…”

The Canonical Long-Chain Fatty Acid Sensing Machinery Processes Arachidonic Acid To Inhibit Virulence in Enterohemorrhagic Escherichia coli

“…A variety of signals present in the gut, including sugars, peptides, and lipids, are sensed by EHEC and are integrated into the complex intracellular signaling cascades that regulate the LEE (2,(7)(8)(9)(10)(11). Transcriptional activation of the LEE is regulated by the master transcription factor Ler, which is the first gene contained within LEE1 (Fig.…”

“…1A) (12,13). The nearly 1,000 bp that comprise the regulatory region upstream from the LEE1 promoter are heavily trafficked by different transcription factors that each sense and respond to specific stimuli, thus enabling the direct coupling of environmental signals to the transcriptional regulation of ler and the entire LEE island (7,9,10,14,15).…”

The therapeutic potential of D-Serine in reducing expression of the cytopathic genotoxin colibactin

“…In the mammalian host, sensing these metabolites can serve as stimuli to trigger the expression of essential virulence genes. In response to L-Arginine in the gut, pathogenic EHEC strains signal the upregulation of LEE-encoded genes to facilitate site-specific colonization of the host [59]. However, in contrast, exposure to D-Serine has been implicated in the downregulation of virulence genes in this E. coli pathotype, with our previous work demonstrating that D-Serine represses the type three secretion system (T3SS) [10].…”

“…In the mammalian host, sensing these metabolites can serve as stimuli to trigger the expression of essential virulence genes. In response to L-Arginine in the gut, pathogenic EHEC strains signal the upregulation of LEE-encoded genes to facilitate site-specific colonization of the host [59].…”