Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut
Open accessAbstract
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. To address the role of these neurotransmitters during enteric infection, we employed C. rodentium Both EHEC and C. rodentium harbor the locus of enterocyte effacement (LEE) that is necessary for AE lesion formation. Here we show that expression of the LEE, as well as that of other virulence genes in C. rodentium, is also activated by epinephrine and/or norepinephrine. Both QseC and QseE are required for LEE gene activation in C. rodentium, and the qseC and qseE mutants are attenuated for murine infection. C. rodentium has a decreased ability to colonize dopamine β-hydroxylase knockout (Dbh(-/-)) mice, which do not produce epinephrine and norepinephrine. Both adrenergic sensors are required for C. rodentium to sense these neurotransmitters and activate the LEE genes during infection. These data indicate that epinephrine and norepinephrine are sensed by bacterial adrenergic receptors during enteric infection to promote activation of their virulence repertoire. This is the first report of the role of these neurotransmitters during mammalian gastrointestinal (GI) infection by a noninvasive pathogen. IMPORTANCE: The epinephrine and norepinephrine neurotransmitters play important roles in gut physiology and motility. Of note, epinephrine and norepinephrine play a central role in stress responses in mammals, and stress has profound effects on GI function. Bacterial enteric pathogens exploit these neurotransmitters as signals to coordinate the regulation of their virulence genes. The bacterial QseC and QseE adrenergic sensors are at the center of this regulatory cascade. C. rodentium is a noninvasive murine pathogen with a colonization mechanism similar to that of EHEC, enabling the investigation of host signals in mice. The presence of these neurotransmitters in the gut is necessary for C. rodentium to fully activate its virulence program, in a QseC/QseE-dependent manner, to successfully colonize its murine host. Our study data provide the first example of epinephrine and norepinephrine signaling within the gut to stimulate infection by a bacterial pathogen in a natural animal infection.
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Norepinephrine can act as a quorum sensing molecule to increase expression of bacterial virulence genes through interaction with bacterial quorum sensing histidine kinase.
“Also, norepinephrine can act as a quorum sensing molecule to increase the expression of bacterial virulence genes through interaction with bacterial quorum sensing histidine kinase (Curtis et al., 2014;Moreira et al., 2016).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Moreira et al., 2016
The Introduction and Results state that bacterial QseC and QseE sense norepinephrine and link these signals to virulence-gene expression. The paper describes norepinephrine as a host neurotransmitter, however, and does not establish that it acts as a quorum-sensing molecule; that part of the claim is unsupported. (LLM, conf=0.84)
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“The role of epinephrine and/or norepinephrine in stimulating virulence gene expression has been extensively studied in the human enteric pathogen enterohemor-rhagic Escherichia coli (EHEC) (11, 19–21, 23, 25, 26).”
Self-citationSegment-specific effects of epinephrine on ion transport in the colon of the rat
Hörger, S., Schultheiß, G., & Diener, M. (1998) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1998.275.6.g1367 · Cited by 68 · cited 1× · see citing works
“These neurotransmitters play important GI functions, modulating intestinal smooth muscle contraction, submucosal blood flow, and chloride and potassium secretion (4).”
Posttranscriptional Control of Microbe-Induced Rearrangement of Host Cell Actin
Gruber, C. C., & Sperandio, V. (2014) · mBio · doi:10.1128/mbio.01025-13 · Cited by 63 · cited 3× · see citing works
“An explanation for this difference is that QseE acts indirectly and posttranscriptionally in expression of the LEE island as well as of other effectors, such as NleA (24, 61).”
Self-citationGruber, C. C., & Sperandio, V. (2015) · Infection and Immunity · doi:10.1128/iai.02918-14 · Cited by 60 · see citing works
Self-citationBacterial Disease in Diverse Hosts
Finlay, B. B. (1999) · Cell · doi:10.1016/s0092-8674(00)80544-9 · Cited by 57 · see citing works
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Kostakioti, M., Hadjifrangiskou, M., Cusumano, C. K., Hannan, T. J., Janetka, J. W., & Hultgren, S. J. (2012) · Infection and Immunity · doi:10.1128/iai.00283-12 · Cited by 46 · see citing works
Spencer, H., Karavolos, M. H., Bulmer, D. M., Aldridge, P. D., Chhabra, S. R., Winzer, K., Williams, P. M., & Khan, C. M. A. (2009) · Journal of Bacteriology · doi:10.1128/jb.01329-09 · Cited by 45 · cited 1× · see citing works
“A third epinephrine/ norepinephrine sensor has been suggested to exist in Salmonella enterica (70).”
Hemrajani, C., Marchès, O., Wiles, S., Girard, F., Dennis, A., Dziva, F., Best, A., Phillips, A. D., Berger, C. N., Mousnier, A., et al. (2008) · Infection and Immunity · doi:10.1128/iai.00742-08 · Cited by 42 · cited 1× · see citing works
“All of the known virulence genes of EHEC have been validated in vivo using C. rodentium murine infections (52–56).”
Dean-Nystrom, E. A., Pohlenz, J., Moon, H. W., & O’Brien, A. D. (2000) · Infection and Immunity · doi:10.1128/iai.68.4.2356-2358.2000 · Cited by 42 · cited 1× · see citing works
“EHEC is able to cause AE lesions in large animals such as suckling neonatal piglets (42) and neonatal calves (39).”
Woods, J. B., Schmitt, C. K., Darnell, S. C., Meysick, K. C., & O’Brien, A. D. (2002) · The Journal of Infectious Diseases · doi:10.1086/338633 · Cited by 40 · see citing works
THOMAS, S. A., & Palmiter, R. D. (1997) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60695-x · Cited by 30 · cited 1× · see citing works
“Littermate Dbh (cid:5) / (cid:4) heterozygous mice were considered controls because they had normal NE and Epi levels (83), as previously assayed with other enteric bacteria (8 The 2-way analysis-of-variance (ANOVA) multiple-comparison test was used to determine the statistical significance of the…”
García-Angulo, V. A., Martínez-Santos, V. I., Villaseñor, T., Santana, F. J., Saquero, A. H., Martínez-Chavarría, L. C., Jiménez-Mejía, R., Lara‐Ochoa, C., Téllez‐Sosa, J., Bustamante, V. H., et al. (2012) · Journal of Bacteriology · doi:10.1128/jb.00190-12 · Cited by 19 · cited 1× · see citing works
“It is worth noting that, while QseC LEE and nleA gene regulation occurs directly by the activity of the QseC-phosphorylated response regulator KdpE in conjunction with Cra (59), activating expression of ler (59), which encodes the direct transcription activator of the LEE and nleA genes (29, 60), QseE regulation is in…”
Mokrievich, A. N., Kondakova, A. N., Valade, E., Platonov, М. E., Вахрамеева, Г. М., Shaikhutdinova, R. Z., Ивановна, М. Р., Blaha, D., Викторовна, Б. И., Титарева, Г. М., et al. (2010) · Biochemistry (Moscow) · doi:10.1134/s0006297910040073 · Cited by 18 · see citing works
Renal Prostacyclin Biosynthesis in a Baboon Model of Shiga Toxin Mediated Hemolytic Uremic Syndrome
Siegler, R. L., Pysher, T. J., Tesh, V. L., & Taylor, F. B. (2002) · The Nephron journals/Nephron journals · doi:10.1159/000063310 · Cited by 13 · see citing works
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The immune responses to bacterial antigens encountered in vivo at mucosal surfaces
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Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut
Yoo, B. B., & Mazmanian, S. K. (2017) · Immunity · doi:10.1016/j.immuni.2017.05.011 · Cited by 479 · see citing works
“Also, wild-type C. rodentium is ineffective at colonizing mice that do not express dopamine beta-hydroxylase (Moreira et al., 2016), the enzyme required for norepinephrine and epinephrine synthesis.”
BackgroundBrain–gut–microbiome interactions in obesity and food addiction
Gupta, A., Osadchiy, V., & Mayer, E. A. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0341-5 · Cited by 268 · see citing works
Obesity and gut–microbiota–brain axis: A narrative review
Asadi, A., Mehr, N. S., Mohamadi, M. H., Shokri, F., Heidary, M., Sadeghifard, N., & Khoshnood, S. (2022) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24420 · Cited by 254 · see citing works
Citrobacter rodentium–host–microbiota interactions: immunity, bioenergetics and metabolism
Mullineaux-Sanders, C., Sanchez‐Garrido, J., Hopkins, E. G. D., Shenoy, A. R., Barry, R. E., & Frankel, G. M. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0252-z · Cited by 170 · see citing works
Pathogens, microbiome and the host: emergence of the ecological Koch's postulates
Vonaesch, P., Anderson, M. C., & Sansonetti, P. J. (2018) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuy003 · Cited by 170 · see citing works
“A recent study has shown that the two neurotransmitters 498 epinephrine and norepinephrine, that are produced by the endocrine cells localized in the intestine are needed for 499 the full expression of virulence/colonization genes (Moreira et al. 2016).”
BackgroundKloock, S., Ziegler, C. G., & Dischinger, U. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108549 · Cited by 157 · see citing works
Salmonella enterica Serovar Typhimurium Strategies for Host Adaptation
Anderson, C. J., & Kendall, M. M. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01983 · Cited by 106 · see citing works
“…regulate virulence by utilizing and/or sensing nitrate (Spees et al., 2013; Winter et al., 2013), epi/NE (Curtis et al., 2014; Halang et al., 2015; Moreira et al., 2016; Rooks et al., 2017), ethanolamine (Maadani et al., 2007; Kendall et al., 2012; DebRoy et al., 2014; Gonyar and Kendall, 2014;…”
BackgroundBacterial Chat: Intestinal Metabolites and Signals in Host-Microbiota-Pathogen Interactions
Lustri, B. C., Sperandio, V., & Moreira, C. G. (2017) · Infection and Immunity · doi:10.1128/iai.00476-17 · Cited by 93 · see citing works
“and NE in the mouse intestine, as shown in infection studies with dopaminehydroxylase knockout (Dbh / ) mice, which are unable to produce Epi and NE (94).”
BackgroundInfluentialSelf-citationRoles of Shiga Toxins in Immunopathology
Lee, M., & Tesh, V. L. (2019) · Toxins · doi:10.3390/toxins11040212 · Cited by 92 · see citing works
“Recently, the Sperandio laboratory has demonstrated that neurotransmitter signaling through epinephrine and norepinephrine within the gut is crucial for the noninvasive enteric pathogens EHEC and Citrobacter rodentium to fully activate virulence mechanisms, including actin polymerization and A/E lesion formation durin…”
BackgroundGut Microbiota and Bone Diseases: A Growing Partnership
Chen, Y., Wang, X., Zhang, C.-L., Liu, Z.-Y., Li, C., & Ren, Z.-G. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.877776 · Cited by 75 · see citing works
Regulation of type III secretion system in Pseudomonas syringae
Xie, Y., Shao, X., & Deng, X. (2019) · Environmental Microbiology · doi:10.1111/1462-2920.14779 · Cited by 77 · see citing works
Cuesta, S., Burdisso, P., Segev, A., Kourrich, S., & Sperandio, V. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.09.014 · Cited by 75 · see citing works
Self-citationRole of the endocannabinoid system in the regulation of intestinal homeostasis
Cuddihey, H., MacNaughton, W. K., & Sharkey, K. A. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.05.015 · Cited by 79 · see citing works
Acne and Stress: Impact of Catecholamines on Cutibacterium acnes
Borrel, V., THOMAS, P. A., Catovic, C., Racine, P., Konto‐Ghiorghi, Y., Lefeuvre, L., Poc, C. D., Zouboulis, C. C., & Feuilloley, M. G. J. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00155 · Cited by 70 · see citing works
Brain–Gut–Microbiome Interactions and Intermittent Fasting in Obesity
Frank, J., Gupta, A., Osadchiy, V., & Mayer, E. A. (2021) · Nutrients · doi:10.3390/nu13020584 · Cited by 68 · see citing works
Biphasic chemotaxis of Escherichia coli to the microbiota metabolite indole
Yang, J., Chawla, R., Rhee, K. Y., Gupta, R., Manson, M. D., Jayaraman, A., & Lele, P. P. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1916974117 · Cited by 67 · see citing works
“However, there exists a spatially varying mix of different microbial and host metabolite signals within the GI tract, some of which are potent chemoattractants (15, 58).”
BackgroundThe Type III Secretion System of Pathogenic Escherichia coli
Slater, S. L., Sagfors, A., Pollard, D. J., Ruano‐Gallego, D., & Frankel, G. M. (2018) · Current topics in microbiology and immunology · doi:10.1007/82_2018_116 · Cited by 67 · see citing works
“Environmental signals are largely integrated by A/E pathogens through sensor kinases (Moreira et al. 2016) including quorum sensing that affects internal specific and global transcriptional regulators: PerC (EPEC)/PchABC (EHEC) or the histone-like nucleoid-structuring protein (H-NS) (Bustamante et al.”
BackgroundQseB/QseC: a two-component system globally regulating bacterial behaviors
Zhu, Y., Dou, Q., Du, L., & Wang, Y. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.02.001 · Cited by 65 · see citing works
The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation
Mackos, A. R., Maltz, R. M., & Bailey, M. T. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.10.006 · Cited by 63 · see citing works
Ramírez, V. T., Godinez, D. R., Brust‐Mascher, I., Nonnecke, E. B., Castillo, P. A., Gardner, M. B., Tu, D., Sladek, J. A., Miller, E. N., Lebrilla, C. B., et al. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007719 · Cited by 59 · see citing works
“rodentium [45] and enterohemorrhagic Escherichia coli [46].”
Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens
Ellermann, M., Pacheco, A. R., Jimenez, A. G., Russell, R. M., Cuesta, S., Kumar, A., Zhu, W., do Vale, G. D., Martin, S. A., Raj, P., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.022 · Cited by 60 · see citing works
“However, several of these mutants are not completely avirulent and unable to colonize the gut (Curtis et al., 2014b; Moreira et al., 2016; Pifer et al., 2018; Menezes-Garcia et al., 2020).”
BackgroundSelf-citationQseC inhibition as an antivirulence approach for colitis-associated bacteria
Rooks, M. G., Veiga, P., Reeves, A. Z., Lavoie, S., Yasuda, K., Asano, Y., Yoshihara, K., Michaud, M., Wardwell-Scott, L., Gallini, C. A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612836114 · Cited by 57 · see citing works
Ceppa, F., Izzo, L., Sardelli, L., Raimondi, I., Tunesi, M., Albani, D., & Giordano, C. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00297 · Cited by 55 · see citing works
Regulation of the Locus of Enterocyte Effacement in Attaching and Effacing Pathogens
Furniss, R. C. D., & Clements, A. (2017) · Journal of Bacteriology · doi:10.1128/jb.00336-17 · Cited by 53 · see citing works
“transcription of the T3SS machinery, allowing infection (78).”
BackgroundCavalu, S. D., Elbaramawi, S. S., Eissa, A. G., Radwan, M. F., Ibrahim, T. S., Khafagy, E., Lopes, B. S., Ali, M. A. M., Hegazy, W. A. H., & Elfaky, M. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113088 · Cited by 52 · see citing works
RetractedAlmalki, A. J., Ibrahim, T. S., Elhady, S. S., Hegazy, W. A. H., & Darwish, K. M. (2022) · Pharmaceuticals · doi:10.3390/ph15020110 · Cited by 49 · see citing works
Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells
Werbner, M., Barsheshet, Y., Werbner, N., Zigdon, M., Averbuch, I., Oren, Z., Brant, B., Elliott, E., Gelberg, S., Titelbaum, M., et al. (2019) · mSystems · doi:10.1128/msystems.00292-18 · Cited by 49 · see citing works
“Major mediators of the stress response are the stress hormones, including epinephrine and norepinephrine (12, 47).”
Balasubramanian, S., Osburne, M., BrinJones, H., Tai, A., & Leong, J. (2018) · bioRxiv · doi:10.1371/journal.ppat.1007494 · Cited by 43 · see citing works
Pathophysiologic Role of Neurotransmitters in Digestive Diseases
Yang, X., Lou, J., Shan, W., Ding, J., Jin, Z., Hu, Y., Du, Q., Liao, Q., Xie, R., & Xu, J. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.567650 · Cited by 48 · see citing works
Stewart, D. B., Wright, J., Fowler, M., McLimans, C. J., Tokarev, V., Amaniera, I., Baker, O. R., Wong, H. T., Brabec, J. L., Drucker, R., et al. (2019) · mSphere · doi:10.1128/msphere.00454-19 · Cited by 46 · see citing works
“In a study focused on enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, Moreira and colleagues (18) provided the first description of host stress hormones (norepinephrine and epinephrine), which directly affect gut physiology through colonic adrenergic receptors, also having a direct effect on bacte…”
BackgroundThe role of two-component regulatory systems in environmental sensing and virulence inSalmonella
de Pina, L. C., da Silva, F. S. H., Galvão, T. C., Pauer, H., Ferreira, R. B. R., & Antunes, L. C. M. (2021) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2021.1895067 · Cited by 39 · see citing works
“In both EHEC and Salmonella, QseEF is known to be involved in regulating the expression of virulence traits, such as T3SS (Reading et al. 2007, 2009; Moreira et al. 2016).”
BackgroundLyte, M., Villageliú, D. N., Crooker, B. A., & Brown, D. R. (2018) · Journal of Dairy Science · doi:10.3168/jds.2017-13589 · Cited by 38 · see citing works
Conversations in the Gut: The Role of Quorum Sensing in Normobiosis
Markus, V., Paul, A. A., Teralı, K., Özer, N., Marks, R. S., Golberg, K., & Kushmaro, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043722 · Cited by 40 · see citing works
“Enteric pathogens use stress hormones as signaling molecules to modify their virulence genes [52].”
BackgroundElfaky, M. A., Elbaramawi, S. S., Eissa, A. G., Ibrahim, T. S., Khafagy, E., Ali, M. A. M., & Hegazy, W. A. H. (2023) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-023-12522-3 · Cited by 38 · see citing works
Long Chain Fatty Acids and Virulence Repression in Intestinal Bacterial Pathogens
Mitchell, M. K., & Ellermann, M. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.928503 · Cited by 39 · see citing works
Enterohemorrhagic Escherichia coli outwits hosts through sensing small molecules
Carlson-Banning, K. M., & Sperandio, V. (2017) · Current Opinion in Microbiology · doi:10.1016/j.mib.2017.12.002 · Cited by 37 · see citing works
“Recent data in the EHEC murine surrogate model, Citrobacter rodentium, highlight how qseC, qseE, and qseEC mutants are attenuated for murine infection because they fail to correctly sense epinephrine and norepinephrine [9].”
BackgroundInfluentialSelf-citationNisco, N. J. D., Rivera‐Cancel, G., & Orth, K. (2018) · mBio · doi:10.1128/mbio.02122-17 · Cited by 37 · see citing works
“Activation of the FusKR signaling cascade by fucose represses transcription of several genes, including Ler, the master regulator of the LEE-encoded T3SS (43).”
BackgroundInfluentialDong, T. S., Gee, G. C., Beltrán‐Sánchez, H., Wang, M. D., Osadchiy, V., Kilpatrick, L. A., Chen, Z., Subramanyam, V., Zhang, Y., Guo, Y., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.10.011 · Cited by 36 · see citing works
“These top-down signals from the brain influence gastrointestinal processes, including motility (22), intestinal permeability (23), and microbial gene expression (24–31).”
Turner, N. C. A., Connolly, J. P. R., & Roe, A. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180546 · Cited by 27 · see citing works
A Review of the Impact of Maternal Prenatal Stress on Offspring Microbiota and Metabolites
Yeramilli, V. A., Cheddadi, R., Shah, J., Brawner, K. M., & Martin, C. A. (2023) · Metabolites · doi:10.3390/metabo13040535 · Cited by 35 · see citing works
Thabit, A. K., Eljaaly, K., Zawawi, A., Ibrahim, T. S., Eissa, A. G., Elbaramawi, S. S., Hegazy, W. A. H., & Elfaky, M. A. (2022) · Microorganisms · doi:10.3390/microorganisms10101976 · Cited by 35 · see citing works
“As a closed-loop, the AIs produced by bacteria stimulate the production of the neuroendocrine hormone in host cells that will be sensed resulting in augmenting virulence [6,8,9].”
BackgroundInfluentialEvgS/EvgA, the unorthodox two-component system regulating bacterial multiple resistance
Zhang, R., & Wang, Y. (2023) · Applied and Environmental Microbiology · doi:10.1128/aem.01577-23 · Cited by 35 · see citing works
“In addition, we speculate that EvgS/EvgA is related to the QseC/QseB TCS. QseC/QseB is able to sense norepinephrine produced by the adrenergic neurons in the gut (142, 143).”
BackgroundBacterial signaling as an antimicrobial target
Ellermann, M., & Sperandio, V. (2020) · Current Opinion in Microbiology · doi:10.1016/j.mib.2020.08.001 · Cited by 34 · see citing works
“enterocyte effacement (LEE), a pathogenicity island that is essential for causing disease [44,45,90].”
BackgroundSelf-citationEndothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis
Sfera, A., Osorio, C., del Campo, C. M. Z. M., Pereida, S., Maurer, S., Maldonado, J. C., & Kozlakidis, Z. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.673217 · Cited by 30 · see citing works
“Indeed, many gut microbes express muscarinic and adrenergic receptors, suggesting that autoantibodies may target these molecules (Furukawa and Haga, 2000; Karavolos et al., 2013; Moreira et al., 2016).”
BackgroundDiet and microbiota-gut-brain axis in relation to tail biting in pigs: A review
Kobek‐Kjeldager, C., Schönherz, A. A., Canibe, N., & Pedersen, L. J. (2021) · Applied Animal Behaviour Science · doi:10.1016/j.applanim.2021.105514 · Cited by 36 · see citing works
Protozoan predation as a driver of diversity and virulence in bacterial biofilms
Hoque, M. M., Espinoza-Vergara, G., & McDougald, D. (2023) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuad040 · Cited by 32 · see citing works
Hypergravity disrupts murine intestinal microbiota
Alauzet, C., Cunat, L., Wack, M., Lozniewski, A., Busby-Venner, H., Agrinier, N., Cailliez‐Grimal, C., & Frippiat, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-45153-8 · Cited by 32 · see citing works
Woodward, S. E., Krekhno, Z., & Finlay, B. B. (2019) · Cellular Microbiology · doi:10.1111/cmi.13107 · Cited by 31 · see citing works
“Interestingly, epinephrine and norepinephrine are required within the gut for full activation of C. rodentium's virulence programme (Moreira et al., 2016).”
BackgroundInfluentialElfaky, M. A., Thabit, A. K., Eljaaly, K., Zawawi, A., Abdelkhalek, A. S., Almalki, A. J., Ibrahim, T. S., & Hegazy, W. A. H. (2022) · Antibiotics · doi:10.3390/antibiotics11111585 · Cited by 32 · see citing works
“Bacterial espionage was observed particularly in gut pathogens, where bacterial sensors sense the surrounding chemical changes, easing their accommodation and enhancing bacterial virulence [23,24].”
BackgroundPre-trained molecular representations enable antimicrobial discovery
Olayo-Alarcón, R., Amstalden, M. K., Zannoni, A., Bajramovic, M., Sharma, C. M., Brochado, A. R., Rezaei, M., & Müller, C. L. (2025) · Nature Communications · doi:10.1038/s41467-025-58804-4 · Cited by 32 · see citing works
Göpel, Y., & Görke, B. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007547 · Cited by 31 · see citing works
Ren, W., Hua, M.-L., Cao, F., & Zeng, W.-W. (2023) · Advancement of science · doi:10.1002/advs.202306128 · Cited by 31 · see citing works
Vitetta, L., Gorgani, N. N., Vitetta, G., & Henson, J. D. (2023) · Biomolecules · doi:10.3390/biom13091307 · Cited by 31 · see citing works
“In animal studies, high epinephrine and norepinephrine levels can stimulate infections by increasing the virulence of some pathogens [20].”
BackgroundInfluentialPeixoto, R. J. M., Alves, E. S., Wang, M., Ferreira, R. B. R., Granato, A., Han, J., Gill, H., Jacobson, K., Lobo, L. A., Domingues, R. M. C. P., et al. (2017) · Applied and Environmental Microbiology · doi:10.1128/aem.01148-17 · Cited by 26 · see citing works
Alotaibi, H. F., Alotaibi, H. F., Darwish, K. M., Khafagy, E., Lila, A. S. A., Ali, M. A. M., Hegazy, W. A. H., & Alshawwa, S. Z. (2023) · Biomedicines · doi:10.3390/biomedicines11123161 · Cited by 26 · see citing works
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“40 Although we did not find Citrobacter rodentium in the mucus of our study, whether Helicobacter could be affected by NE or other neurotransmitters warrants further studies.”
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“Similarly, qseC null mutants were also impaired for colonizing the mouse intestine, highlighting the importance of host signal sensing during host colonization [12].”
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“rodentium virulence for the QseBC and QseFE TCSs that respond to the catecholamines epinephrine and norepinephrine in the gut (33).”
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“The adrenergic sensor QseE phosphorylates the RR QseF, which coordinates the expression of virulence genes involved in the formation of lesions in intestinal epithelia by EHEC, as well as the bacterial stress response SOS [37,38].”
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“It has been reported that NE can act as a ligand for bacterial quorum-sensing proteins (97), inducing bacterial proliferation and expression of virulence genes (98, 99).”
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“The QseBC 2-component system, first described in EHEC [34], plays a crucial role in regulating the virulence genes expression of important human enteropathogens [35].”
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“In addition, epinephrine can induce QseEF expression [21,24].”
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“Therefore like other toxoid vaccine like tetanus (Moreira et al., 2016) it may be a suitable target for the development of toxoid vaccine against salmonellosis.”
- Authors
- Moreira, C. G., Russell, R., Mishra, A. A., Narayanan, S., Ritchie, J. M., Waldor, M. K., Curtis, M. M., Winter, S. E., Weinshenker, D., & Sperandio, V.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Kansas State University (US)
- University of Surrey (GB)
- Brigham and Women's Hospital (US)
- Emory University (US)
- Corresponding author
- Sperandio, Vanessa
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2016-07-06
- Volume
- 7
- Issue
- 3
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4959670
- OpenAlex
- W2411358133
- Cited by
- 157
- References
- 81
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 16 · 2023: 23 · 2022: 17 · 2021: 11 · 2020: 9 · 2019: 16 · 2018: 11 · 2017: 8 · 2016: 3 · 2015: 1 · 2012: 1
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- K-State Research Exchange (Kansas State University) (submittedVersion, cc-by)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Open Research (University of Surrey) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- UNESP Institutional Repository (São Paulo State University) (submittedVersion)
- Funders
- HHS | National Institutes of Health (T32 AI7520)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI101472, AI05135, AI053067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Enterobacteriaceae and Cronobacter Research
- Keywords
- QseC, epinephrine, norepinephrine, enteric pathogens, Citrobacter rodentium, enterohemorrhagic Escherichia coli, locus of enterocyte effacement, virulence gene regulation, dopamine beta-hydroxylase, intestinal colonization, attaching and effacing lesions, host-pathogen interaction
- MeSH terms
- Animals, Dopamine beta-Hydroxylase, Enterobacteriaceae Infections, Epinephrine, Escherichia coli Infections, Genes, Bacterial, Norepinephrine, Phosphoproteins, Receptors, Adrenergic, Vasoconstrictor Agents, Virulence, Gene Expression Regulation, Bacterial, Mice, Knockout, Enterocytes, Escherichia coli Proteins, Gastrointestinal Tract, Citrobacter rodentium, Mice, Enterohemorrhagic Escherichia coli, Host-Pathogen Interactions
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