title: QseC inhibition as an antivirulence approach for colitis-associated bacteria.
abstract: Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/-IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Rooks
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Danone Nutricia Research, 91767 Palaiseau Cedex, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Veiga
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02139.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Analise Z
authors.initials: AZ
authors.lastname: Reeves
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Sydney
authors.initials: S
authors.lastname: Lavoie
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Koji
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Yoshihara
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Monia
authors.initials: M
authors.lastname: Michaud
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wardwell-Scott
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Carey Ann
authors.initials: CA
authors.lastname: Gallini
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215.|Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.affiliation: Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sudo
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02139.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Cammie F
authors.initials: CF
authors.lastname: Lesser
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; wgarrett@hsph.harvard.edu.|Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D003092:Colitis / Q000382:microbiology / Q000473:pathology* / Q000628:therapy*; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005407:Flagella / Q000235:genetics / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053038:Quorum Sensing / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D014774:Virulence / Q000235:genetics
chemical_list: D002395:Catecholamines; D029968:Escherichia coli Proteins; C531088:LED209; C455504:QseC protein, E coli; D013449:Sulfonamides
keywords: Escherichia coli; QseC; antivirulence; colitis; gut microbiome