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.colitis | Escherichia coli | QseC | antivirulence | gut microbiome

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…The inactivation of QseC in a pathogenic IBD-associated E coli strain can reduce its virulence in vitro and abrogate its ability to persist in a low-complexity microbiome in vivo 213. These results provide insight into the use of an antivirulence approach to target not only pathogens, but also a much larger collection of colitogenic bacteria.…”

“…Perturbing the Enterobacteriaceae adrenergic receptor QseC with the biochemical inhibitor LED209 can attenuate experimental colitis 213. The inactivation of QseC in a pathogenic IBD-associated E coli strain can reduce its virulence in vitro and abrogate its ability to persist in a low-complexity microbiome in vivo 213.…”

A real-time PCR assay for accurate quantification of the individual members of the Altered Schaedler Flora microbiota in gnotobiotic mice

“…Upon colonization, each species likely occupies different niches of the mouse GI tract and contributes to immune maturation, colonization resistance and host physiology (Orcutt et al, 1987). In addition, this model GI microbial community offers a unique opportunity to assess the specific contribution of individual bacterial species during states of homeostasis and disease (Atherly et al, 2016; Brugiroux et al, 2016; Endt et al, 2010; Ge et al, 2006; Rooks et al, 2017). However, a robust molecular quantification method for this community is needed, especially considering that cultivating some ASF members can be cumbersome.…”

“…The Altered Schaedler Flora (ASF) microbiota is one example of a defined community that offers the opportunity to study and dissect host-and-microbe relationships at a mechanistic level (Wymore et al, 2015). Moreover, it permits the addition of other specific organisms such as pathogens (Brugiroux et al, 2016, Endt et al, 2010) or pathobionts (Atherly et al, 2016, Ge et al, 2006, Rooks et al, 2017), thereby allowing for the measurement of individual member contributions to host functions such as immune system maturation (i.e., development of regulatory CD4 + T cells) and the onset of intestinal inflammation (Geuking et al, 2011, Liu et al, 2011; Wymore et al, 2015). Although the ASF community is limited in its metabolic capabilities and phylogenetic representation as compared to a conventional gut microbiota (Brugiroux et al, 2016; Dewhirst et al, 1999), the ASF community is resilient, and its members are long-term colonizers (Stehr et al, 2009) despite varying in abundance across different anatomical sites and host genotypes (Alexander et al, 2006; Sarma-Rupavtarm et al 2004).…”

Involvement of Two-Component Signaling on Bacterial Motility and Biofilm Development

“…The signaling transduction cascade includes chemotaxis by using the serine receptor Tsr (56,57) and activation of QseC (58). In the search for novel therapeutic targets and drugs, blocking the binding of epinephrine or norepinephrine to QseC with a proposed LED209 drug resulted in decreased QseC/QseB signaling and reduced motility and virulence (59), as well as attenuation of colitis in mice (60).…”