Microbiota and Pathogen Proteases Modulate Type III Secretion Activity in Enterohemorrhagic Escherichia coli.

Enteric pathogens have complex interactions with the gut microbiota. Most of what is known about them has focused on microbiota-derived metabolites or small molecules that serve as nutrients and/or signals to aid in growth or transcriptionally regulate virulence gene expression. A common virulence strategy is to express a type III secretion system (T3SS), which is a molecular syringe deployed by many Gram-negative pathogens to hijack host cell function.

Redox, amino acid, and fatty acid metabolism intersect with bacterial virulence in the gut.

The gut metabolic landscape is complex and is influenced by the microbiota, host physiology, and enteric pathogens. Pathogens have to exquisitely monitor the biogeography of the gastrointestinal tract to find a suitable niche for colonization. To dissect the important metabolic pathways that influence virulence of enterohemorrhagic (EHEC), we conducted a high-throughput screen.

Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut.

Unlabelled: Enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, which is largely used as a surrogate EHEC model for murine infections, are exposed to several host neurotransmitters in the gut. An important chemical exchange within the gut involves the neurotransmitters epinephrine and/or norepinephrine, extensively reported to increase virulence gene expression in EHEC, acting through two bacterial adrenergic sensors: QseC and QseE. However, EHEC is unable to establish itself and cause its hallmark lesions, attaching and effacing (AE) lesions, on murine enterocytes.

The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape.

The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations.

QseC inhibitors as an antivirulence approach for Gram-negative pathogens.

Unlabelled: Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence.

Restrictive Streptomycin Resistance Mutations Decrease the Formation of Attaching and Effacing Lesions in Escherichia coli O157:H7 Strains.

Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Str) phenotype and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Str mutants of O157:H7 have been generated for studies to promote colonization and to provide a selective marker for this pathogen.

Fucose sensing regulates bacterial intestinal colonization.

The mammalian gastrointestinal tract provides a complex and competitive environment for the microbiota. Successful colonization by pathogens requires scavenging nutrients, sensing chemical signals, competing with the resident bacteria and precisely regulating the expression of virulence genes. The gastrointestinal pathogen enterohaemorrhagic Escherichia coli (EHEC) relies on inter-kingdom chemical sensing systems to regulate virulence gene expression.

Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.

Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes.

Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.

The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression.

IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.

In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner.

Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.

The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection.