QseC inhibition as an antivirulence approach for colitis-associated bacteria

Michelle G. Rooks, Patrick Veiga, Analise Z. Reeve, Sydney Lavoie, Koji Yasuda, Yasunari Asano, Kazufumi Yoshihara, Monia Michaud, Leslie Wardwell-Scott, Carey Ann Gallini, Jonathan N. Glickman, Nobuyuki Sudo, Curtis Huttenhower, Cammie F. Lesser, Wendy S. Garretta

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)142-147
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number1
DOIs
Publication statusPublished - Jan 3 2017

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Colitis
Inflammatory Bowel Diseases
Bacteria
Microbiota
Enterobacteriaceae
Catecholamines
Virulence
Molecular Motor Proteins
Dysbiosis
Escherichia coli
Bacterial Proteins
Benzoates
Disease Management
Inhibition (Psychology)
Homeostasis
Communication
Inflammation
Gene Expression
Health
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

QseC inhibition as an antivirulence approach for colitis-associated bacteria. / Rooks, Michelle G.; Veiga, Patrick; Reeve, Analise Z.; Lavoie, Sydney; Yasuda, Koji; Asano, Yasunari; Yoshihara, Kazufumi; Michaud, Monia; Wardwell-Scott, Leslie; Gallini, Carey Ann; Glickman, Jonathan N.; Sudo, Nobuyuki; Huttenhower, Curtis; Lesser, Cammie F.; Garretta, Wendy S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 1, 03.01.2017, p. 142-147.

Research output: Contribution to journalArticle

Rooks, MG, Veiga, P, Reeve, AZ, Lavoie, S, Yasuda, K, Asano, Y, Yoshihara, K, Michaud, M, Wardwell-Scott, L, Gallini, CA, Glickman, JN, Sudo, N, Huttenhower, C, Lesser, CF & Garretta, WS 2017, 'QseC inhibition as an antivirulence approach for colitis-associated bacteria', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 1, pp. 142-147. https://doi.org/10.1073/pnas.1612836114
Rooks, Michelle G. ; Veiga, Patrick ; Reeve, Analise Z. ; Lavoie, Sydney ; Yasuda, Koji ; Asano, Yasunari ; Yoshihara, Kazufumi ; Michaud, Monia ; Wardwell-Scott, Leslie ; Gallini, Carey Ann ; Glickman, Jonathan N. ; Sudo, Nobuyuki ; Huttenhower, Curtis ; Lesser, Cammie F. ; Garretta, Wendy S. / QseC inhibition as an antivirulence approach for colitis-associated bacteria. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 1. pp. 142-147.
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