QseC inhibition as an antivirulence approach for colitis-associated bacteria.

Autor:	Rooks MG; 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., Veiga P; 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., Reeves AZ; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02139.; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115., Lavoie S; 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., Yasuda K; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Asano Y; Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan., Yoshihara K; Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan., Michaud M; 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., Wardwell-Scott L; 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., Gallini CA; 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., Glickman JN; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215.; Department of Pathology, Harvard Medical School, Boston, MA 02115., Sudo N; Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan., Huttenhower C; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Lesser CF; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02139.; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115., Garrett WS; 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.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jan 03; Vol. 114 (1), pp. 142-147. Date of Electronic Publication: 2016 Dec 15.
DOI:	10.1073/pnas.1612836114
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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