{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:54:58Z","timestamp":1787806498909,"version":"build-2784847793"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"NUS Medicine Synthetic Biology Translational Research Program","award":["NUHSRO\/2024\/064\/NUSMed\/05\/SynCTI2.0"],"award-info":[{"award-number":["NUHSRO\/2024\/064\/NUSMed\/05\/SynCTI2.0"]}]},{"DOI":"10.13039\/100018237","name":"Asian Office of Aerospace Research and Development","doi-asserted-by":"publisher","award":["FA2386-18-1-4058"],"award-info":[{"award-number":["FA2386-18-1-4058"]}],"id":[{"id":"10.13039\/100018237","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Centre for Engineering Biology","award":["NRF-MSG-2023-0003"],"award-info":[{"award-number":["NRF-MSG-2023-0003"]}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    Host stress is associated with elevated catecholamine neurohormones that influence gut physiology and host\u2013microbe interactions, yet how bacterial systems detect and interpret these signals remains incompletely understood. Enteric pathogens exploit inter-kingdom adrenergic signaling to sense host-derived norepinephrine and epinephrine, but whether such pathways can be rationally rewired to produce predictable, programmable outputs has not been systematically explored. Here, we reconstitute adrenergic signaling in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    Nissle 1917 by repurposing the enterohemorrhagic\n                    <jats:italic>E. coli<\/jats:italic>\n                    QseBC two-component system. Transcriptomic profiling revealed robust catecholamine-dependent activation of QseBC-regulated pathways in the engineered strain. Guided by these data, we redesigned a QseBC-responsive promoter through rational truncation, sigma-factor replacement, and optimization of QseBC expression, generating a synthetic promoter with enhanced sensitivity and dose-dependent responsiveness to stress hormones. Structure-guided mutagenesis of the QseC sensor kinase identified key residues required for catecholamine recognition, providing mechanistic insight into adrenergic hormone sensing. To demonstrate functional signal transduction beyond transcriptional reporting, we coupled the sensing module to a secretion cassette encoding a corticotropin-releasing factor (CRF) receptor antagonist as a model bioactive output and validated bioactivity in vitro. Together, this work elucidates principles governing bacterial stress hormone sensing and demonstrates how inter-kingdom signaling pathways can be engineered to yield programmable biological outputs.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003926","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:22:22Z","timestamp":1787678542000},"page":"e3003926","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineering inter-kingdom adrenergic signaling in commensals couples host stress hormone sensing to programmable biological outputs"],"prefix":"10.1371","volume":"24","author":[{"given":"Santosh Kumar","family":"Srivastava","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo Wei","family":"Foo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haosheng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok Soon","family":"Wun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Young","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Goodson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil","family":"Aggarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-6319","authenticated-orcid":true,"given":"Matthew Wook","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"pbio.3003926.ref001","doi-asserted-by":"crossref","first-page":"104501","DOI":"10.1016\/j.psyneuen.2019.104501","article-title":"Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: A transdisciplinary challenge","volume":"111","author":"A Labanski","year":"2020","journal-title":"Psychoneuroendocrinology"},{"issue":"2","key":"pbio.3003926.ref002","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/j.2040-4603.2016.tb00694.x","article-title":"Regulation of the hypothalamic-pituitary-adrenocortical stress response","volume":"6","author":"JP Herman","year":"2016","journal-title":"Compr Physiol"},{"key":"pbio.3003926.ref003","unstructured":"Funk M. Global burden of mental disorders and the need for a comprehensive, coordinated response from health and social sectors at the country level. Retrieved on. 2016;30."},{"issue":"20","key":"pbio.3003926.ref004","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1113\/JP281951","article-title":"The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective","volume":"601","author":"S-J Leigh","year":"2023","journal-title":"J Physiol"},{"issue":"9","key":"pbio.3003926.ref005","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1128\/IAI.72.9.5446-5451.2004","article-title":"The neuroendocrine stress hormone norepinephrine augments Escherichia coli O157:H7-induced enteritis and adherence in a bovine ligated ileal loop model of infection","volume":"72","author":"I Vlisidou","year":"2004","journal-title":"Infect Immun"},{"issue":"9","key":"pbio.3003926.ref006","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/jcp.25518","article-title":"Neurotransmitters: the critical modulators regulating gut-brain axis","volume":"232","author":"R Mittal","year":"2017","journal-title":"J Cell Physiol"},{"issue":"12","key":"pbio.3003926.ref007","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00476-17","article-title":"Bacterial chat: intestinal metabolites and signals in host-microbiota-pathogen interactions","volume":"85","author":"BC Lustri","year":"2017","journal-title":"Infect Immun"},{"key":"pbio.3003926.ref008","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.csbj.2020.02.018","article-title":"Neuropeptides in gut-brain axis and their influence on host immunity and stress","volume":"18","author":"P Wei","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"issue":"1","key":"pbio.3003926.ref009","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/1874467210666170224095741","article-title":"Brain and gut CRF signaling: biological actions and role in the gastrointestinal tract","volume":"11","author":"Y Tache","year":"2018","journal-title":"Curr Mol Pharmacol"},{"issue":"1","key":"pbio.3003926.ref010","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5056\/jnm14084","article-title":"Role of Corticotropin-releasing factor in gastrointestinal permeability","volume":"21","author":"BK Rodi\u00f1o-Janeiro","year":"2015","journal-title":"J Neurogastroenterol Motil"},{"issue":"9","key":"pbio.3003926.ref011","doi-asserted-by":"crossref","first-page":"4597","DOI":"10.1128\/IAI.00630-07","article-title":"Differential effects of epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis, colonization, and gene expression","volume":"75","author":"T Bansal","year":"2007","journal-title":"Infect Immun"},{"issue":"3","key":"pbio.3003926.ref012","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00826-16","article-title":"Bacterial adrenergic sensors regulate virulence of enteric pathogens in the gut","volume":"7","author":"CG Moreira","year":"2016","journal-title":"mBio"},{"key":"pbio.3003926.ref013","article-title":"Bacterial adrenergic receptor kinases: Tools for host-pathogen cross talk from the bacterial virulence repertoire","author":"R Mukherji","year":"2023"},{"issue":"27","key":"pbio.3003926.ref014","doi-asserted-by":"crossref","first-page":"10420","DOI":"10.1073\/pnas.0604343103","article-title":"The QseC sensor kinase: a bacterial adrenergic receptor","volume":"103","author":"MB Clarke","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pbio.3003926.ref015","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1136\/gut.2003.036400","article-title":"Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology?","volume":"53","author":"Y Tach\u00e9","year":"2004","journal-title":"Gut"},{"issue":"6","key":"pbio.3003926.ref016","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1053\/gast.2000.20251","article-title":"Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats","volume":"119","author":"C Maillot","year":"2000","journal-title":"Gastroenterology"},{"issue":"3","key":"pbio.3003926.ref017","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1210\/endo-129-3-1312","article-title":"Differential antagonist activity of alpha-helical corticotropin-releasing factor9-41 in three bioassay systems","volume":"129","author":"L Fisher","year":"1991","journal-title":"Endocrinology"},{"issue":"7","key":"pbio.3003926.ref018","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1136\/gut.2003.018911","article-title":"Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome","volume":"53","author":"Y Sagami","year":"2004","journal-title":"Gut"},{"issue":"2","key":"pbio.3003926.ref019","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1177\/0897190009360023","article-title":"Implications of corticotropin releasing factor in targeted anticancer therapy","volume":"23","author":"B-J Kim","year":"2010","journal-title":"J Pharm Pract"},{"issue":"6","key":"pbio.3003926.ref020","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1111\/j.1365-2958.2005.04792.x","article-title":"Transcriptional regulation of flhDC by QseBC and sigma (FliA) in enterohaemorrhagic Escherichia coli","volume":"57","author":"MB Clarke","year":"2005","journal-title":"Mol Microbiol"},{"issue":"11","key":"pbio.3003926.ref021","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1128\/IAI.70.11.6068-6074.2002","article-title":"Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice","volume":"70","author":"S Agelaki","year":"2002","journal-title":"Infect Immun"},{"issue":"10","key":"pbio.3003926.ref022","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004649","article-title":"Comprehensive mapping of the Escherichia coli flagellar regulatory network","volume":"10","author":"DM Fitzgerald","year":"2014","journal-title":"PLoS Genet"},{"issue":"2","key":"pbio.3003926.ref023","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1128\/IAI.05921-11","article-title":"Enterohemorrhagic Escherichia coli virulence regulation by two bacterial adrenergic kinases, QseC and QseE","volume":"80","author":"J Njoroge","year":"2012","journal-title":"Infect Immun"},{"issue":"3","key":"pbio.3003926.ref024","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1046\/j.1365-2958.2002.02803.x","article-title":"Quorum sensing Escherichia coli regulators B and C (QseBC): a novel two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli","volume":"43","author":"V Sperandio","year":"2002","journal-title":"Mol Microbiol"},{"issue":"11","key":"pbio.3003926.ref025","doi-asserted-by":"crossref","DOI":"10.1128\/JB.00018-17","article-title":"Functional analysis of the alternative sigma-28 factor FliA and its anti-sigma factor FlgM of the nonflagellated legionella species L. oakridgensis","volume":"199","author":"H Tlap\u00e1k","year":"2017","journal-title":"J Bacteriol"},{"key":"pbio.3003926.ref026","first-page":"145","article-title":"Programming gene expression with combinatorial promoters","volume":"3","author":"RS Cox","year":"2007","journal-title":"Mol Syst Biol"},{"issue":"8","key":"pbio.3003926.ref027","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1000553","article-title":"The QseC adrenergic signaling cascade in Enterohemorrhagic E. coli (EHEC)","volume":"5","author":"DT Hughes","year":"2009","journal-title":"PLoS Pathog"},{"issue":"2","key":"pbio.3003926.ref028","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.yfrne.2013.10.006","article-title":"Corticotropin-releasing factor peptide antagonists: design, characterization and potential clinical relevance","volume":"35","author":"JE Rivier","year":"2014","journal-title":"Front Neuroendocrinol"},{"issue":"41","key":"pbio.3003926.ref029","doi-asserted-by":"crossref","first-page":"16592","DOI":"10.1073\/pnas.1315320110","article-title":"Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor","volume":"110","author":"KR Guckes","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"pbio.3003926.ref030","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1136\/gut.2006.114926","article-title":"Norepinephrine increases the pathogenic potential of Campylobacter jejuni","volume":"56","author":"TA Cogan","year":"2007","journal-title":"Gut"},{"issue":"4","key":"pbio.3003926.ref031","article-title":"The stress hormone norepinephrine increases the growth and virulence of Aeromonas hydrophila","volume":"8","author":"J Gao","year":"2019","journal-title":"Microbiologyopen"},{"issue":"3","key":"pbio.3003926.ref032","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/sj.bjp.0702831","article-title":"Catechol-O-methyltransferase activity in CHO cells expressing norepinephrine transporter","volume":"128","author":"E Percy","year":"1999","journal-title":"Br J Pharmacol"},{"issue":"3","key":"pbio.3003926.ref033","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.4049\/jimmunol.176.3.1869","article-title":"Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1","volume":"176","author":"C Tsatsanis","year":"2006","journal-title":"J Immunol"},{"issue":"16","key":"pbio.3003926.ref034","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility","volume":"30","author":"GM Morris","year":"2009","journal-title":"J Comput Chem"},{"issue":"1","key":"pbio.3003926.ref035","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nbt1174","article-title":"Extracellular accumulation of recombinant proteins fused to the carrier protein YebF in Escherichia coli","volume":"24","author":"G Zhang","year":"2006","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pbio.3003926.ref036","doi-asserted-by":"crossref","first-page":"467","DOI":"10.2144\/000112401","article-title":"Isolation and solubilization of proteins after TRIzol extraction of RNA and DNA from patient material following prolonged storage","volume":"42","author":"AB Hummon","year":"2007","journal-title":"Biotechniques"},{"key":"pbio.3003926.ref037","unstructured":"Scientific TF. TRIzol Reagent User Guide-Pub. no. MAN0001271-Rev. A. 0. User Guid. 15596018. 2016."},{"issue":"2","key":"pbio.3003926.ref038","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nprot.2006.83","article-title":"The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on","volume":"1","author":"P Chomczynski","year":"2006","journal-title":"Nat Protoc"},{"issue":"4","key":"pbio.3003926.ref039","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods"}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003926","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:22:31Z","timestamp":1787678551000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3003926"}},"subtitle":[],"editor":[{"given":"Baojun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3003926","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}