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 journalArticlepeer-review

27 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

All Science Journal Classification (ASJC) codes

  • General

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