The deadly gastrointestinal pathogen enterohemorrhagic E. coli (EHEC) O157:H7 exploits sensing the host's stress hormones epinephrine (epi) and norepinephrine (NE) to activate its virulence traits. Stress responses have a profound effect in an organism's physiology and survival, and are also sensed by bacteria as a means to gauge the metabolic and immune state of the host. These hormones in mammals are sensed by adrenergic receptors that are G-coupled protein receptors (GPCRs). Bacteria, however, sense these hormones through histidine sensor kinases (HKs), which act in concert with a response regulator (RR) protein constituting a two-component system. Upon sensing its signal, the HK autophosphorylates in a histidine residue, and then transfers this phosphate to an aspartate residue in its cognate RR. The majority of the RRs are transcription factors, which are activated upon phosphorylation. We have first reported EHEC's two adrenergic receptors: the HKs QseC and QseE with QseE being downstream of QseC in this signaling cascade (given that transcription of qseE is activated through QseC). QseC homologues are present in at least 25 important human and plant pathogens, while the distribution of QseE is limited to enteric bacteria. EHEC qseC and qseE mutants have been shown to be attenuated for virulence in vitro and in vivo using an infant rabbit model of infection However, the study of the true interplay between EHEC and the host through this signaling system has been challenging due to the lack of murine models to study EHEC pathogenesis in the GI tract. Hence, many investigators utilize the natural mouse pathogen Citrobacter rodentium as a surrogate model for EHEC GI pathogenesis in mice. All of the known virulence genes of EHEC have been validated in vivo using C. rodentium murine infections. The utilization of the C. rodentium model capitalizes in merging the powerful genetically tractability of host and pathogen to unravel the mechanisms involved in host recognition and infection. We have shown that epi and NE activate expression of all virulence genes in C. rodentium, in a similar scenario to what we have observed with EHEC (Preliminary results). C. rodentium qseC and qseE mutants are also attenuated for virulence in vitro and in vivo (murine infection) (Preliminary studies), making this a genetically tractable model to dissect the contribution of host chemical signals during pathogenesis. In accordance, the Specific Aim of this application is: Characterize the contribution of the host Epi/NE hormones to C. rodentium pathogenesis during murine infection.

Public Health Relevance

Several human deadly pathogens tightly regulate expression of their virulence traits;when these pathogens infect a suitable host, many chemical signals are sensed so they can gage the host and site of infection, and subsequently activate expression of their virulence genes. Some of these signals are the host stress hormones epinephrine and norepinephrine to activate their virulence genes. In this grant we will study how Citrobacter rodentium (a mouse pathogen used as a model for E. coli O157:H7) sense and respond to these hormones in vitro and during animal infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-A (80))
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Baqar, Shahida
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University of Texas Sw Medical Center Dallas
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United States
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Moreira, Cristiano G; Russell, Regan; Mishra, Animesh Anand et al. (2016) Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut. MBio 7:
Cameron, Elizabeth A; Sperandio, Vanessa (2015) Frenemies: Signaling and Nutritional Integration in Pathogen-Microbiota-Host Interactions. Cell Host Microbe 18:275-84
Hernandez-Doria, Juan D; Sperandio, Vanessa (2013) Nutrient and chemical sensing by intestinal pathogens. Microbes Infect 15:759-64