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1.
Nat Commun ; 15(1): 4462, 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38796512

RESUMEN

Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection. Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal. Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate. This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche.


Asunto(s)
Arabinosa , Citrobacter rodentium , Escherichia coli Enterohemorrágica , Arabinosa/metabolismo , Animales , Ratones , Citrobacter rodentium/patogenicidad , Citrobacter rodentium/metabolismo , Citrobacter rodentium/genética , Humanos , Virulencia , Escherichia coli Enterohemorrágica/patogenicidad , Escherichia coli Enterohemorrágica/metabolismo , Escherichia coli Enterohemorrágica/genética , Regulación Bacteriana de la Expresión Génica , Factores de Virulencia/metabolismo , Factores de Virulencia/genética , Infecciones por Enterobacteriaceae/microbiología , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Sistemas de Secreción Tipo III/metabolismo , Sistemas de Secreción Tipo III/genética , Infecciones por Escherichia coli/microbiología , Femenino
2.
Nature ; 628(8006): 180-185, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38480886

RESUMEN

The gut microbiome has major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens1-3, including enterohaemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea and acute renal failure4,5 (haemolytic uremic syndrome). Although gut microorganisms can provide colonization resistance by outcompeting some pathogens or modulating host defence provided by the gut barrier and intestinal immune cells6,7, this phenomenon remains poorly understood. Here, we show that activation of the neurotransmitter receptor dopamine receptor D2 (DRD2) in the intestinal epithelium by gut microbial metabolites produced upon dietary supplementation with the essential amino acid L-tryptophan protects the host against Citrobacter rodentium, a mouse AE pathogen that is widely used as a model for EHEC infection8,9. We further find that DRD2 activation by these tryptophan-derived metabolites decreases expression of a host actin regulatory protein involved in C. rodentium and EHEC attachment to the gut epithelium via formation of actin pedestals. Our results reveal a noncanonical colonization resistance pathway against AE pathogens that features an unconventional role for DRD2 outside the nervous system in controlling actin cytoskeletal organization in the gut epithelium. Our findings may inspire prophylactic and therapeutic approaches targeting DRD2 with dietary or pharmacological interventions to improve gut health and treat gastrointestinal infections, which afflict millions globally.


Asunto(s)
Citrobacter rodentium , Mucosa Intestinal , Receptores de Dopamina D2 , Triptófano , Animales , Femenino , Humanos , Masculino , Ratones , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Carga Bacteriana/efectos de los fármacos , Citrobacter rodentium/crecimiento & desarrollo , Citrobacter rodentium/metabolismo , Citrobacter rodentium/patogenicidad , Suplementos Dietéticos , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/prevención & control , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/prevención & control , Escherichia coli O157/patogenicidad , Escherichia coli O157/fisiología , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Receptores de Dopamina D2/metabolismo , Triptófano/administración & dosificación , Triptófano/metabolismo , Triptófano/farmacología
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