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Faculty 1000

1. "Human intestinal epithelial cell-derived molecule(s) increase enterohemorrhagic Escherichia coli virulence," T. Bansal, D. N. Kim, T. Slininger, T. K. Wood, and A. Jayaraman, FEMS Immunol Med Microbiol. 66: 399-410 (2012).

The data presented in this manuscript provide evidence that soluble factors (possibly proteins) secreted by HCT-8 intestinal epithelial cells (IEC) significantly influence EHEC (enterohemorrhagic Escherichia coli) virulence. Specifically, conditioned medium from HCT-8 cells increased the expression of 32 out of 41 EHEC loci of enterocyte effacement virulence genes compared with fresh medium. Consequently, it caused a five-fold increase in EHEC attachment to the IED. Soluble factor(s) from IEC also increase the expression of phage-encoded Shiga toxin 1 and Shiga toxin 2. These data further suggest that host-pathogen communication occurs even prior to their physical interaction. It will be important in future to determine whether other types of IEC cause similar changes in EHEC gene expression profiles. It will also be important to identify the IEC-derived proteins(s) responsible for changes in EHEC gene expression. Finally, it will be important to determine whether, in response to EHEC infections, the IEC secrete some factors that might protect the host from bacterial infection.

Evaluated 03 Jan 2013 by Olga Kovbasnjuk, Johns Hopkins University, MD, USA. F-1000 Pharmacology & Drug Discovery. Interesting Hypothesis, New Finding

2. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Wang X, Lord DM, Cheng HY, Osbourne DO, Hong SH, Sanchez-Torres V, Quiroga C, Zheng K, Herrmann T, Peti W, Benedik MJ, Page R, Wood TK, Nature Chemical Biology 2012 Sep 2 8: 855-861

In order to increase tolerance to antibiotic treatment, bacteria have developed strategies that include genetic mutation and target protein overexpression, biofilm development, and persister cell formation. Here, the authors describe a novel toxin/antitoxin system (GhoT/GhoS) that regulates the two latter mechanisms in Escherichia coli. The authors show that toxin GhoT greatly increases cellular persistence through membrane disruption, and GhoT deletion strains display decreased swimming mobility and biofilm-forming capacity. These effects are regulated by the presence of the antitoxin GhoS, whose nuclear magnetic resonance (NMR) structure reveals a ferredoxin-like fold with a structurally conserved RNase catalytic site, which goes hand-in-hand with the remarkable finding that GhoS regulates GhoT activity by specifically cleaving its mRNA. The GhoT/GhoS pair thus represents a novel toxin/antitoxin system, where toxin activity is regulated by the antitoxin's mRNA degradation capability, and is hence classified as a 'type V' system.

3. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Bansal T, Alaniz RC, Wood TK, Jayaraman A, Proc Natl Acad Sci U S A 2009 Dec 4 107(1):228-233

The authors show that indole, a small molecule produced in high concentrations by several commensal bacteria in the gastrointestinal tract, has a range of beneficial and anti-inflammatory effects on intestinal epithelial cells that are mediated by changes in gene expression. The findings may imply a means to reproduce the beneficial effects of probiotics without the need to administer live bacteria. The authors hypothesized that bacterially produced molecules might be capable of "interkingdom communication" with host epithelial cells, in much the same way that commensal bacteria have been shown to respond to some human hormones. They tested indole as a key stationary phase metabolite of several commensals that is present at up to millimolar concentrations in the feces. At biologically relevant concentrations, indole, but not closely related molecules, induced a large number of gene expression events in a human intestinal epithelial cell line, some of which related to improved epithelial barrier properties. Further, indole suppressed the ability of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), to activate the proinflammatory transcription factor nuclear factor kappa B (NF-kappaB) and secretion of the neutrophil chemokine interleukin (IL)-8, while inducing production of the anti-inflammatory cytokine IL-10. The findings are important because some researchers have raised concerns about the use of live probiotics for therapeutic gain in patients with compromised immunity and/or defective intestinal barrier function (ironically, the latter being a condition for which probiotics are indicated). If it is possible to replace probiotics with a small molecule that is presumed safe, since it occurs naturally in the gut, this may improve therapy. On the other hand, it has yet to be established that indole is necessary for, or sufficient to reproduce, the protean beneficial effects that have been ascribed to probiotics. Further studies should establish this link as well as determining whether the therapeutic effects of indole can be optimized with the application of medicinal chemistry approaches.

Evaluated 13 Jan 2010 by Kim Barrett, Faculty of 1000.

4. Structure and function of the Escherichia coli protein YmgB: a protein critical for biofilm formation and acid-resistance. Lee J, Page R, García-Contreras R, Palermino JM, Zhang XS, Doshi O, Wood TK, Peti W, J Mol Biol 2007 Oct 12 373(1):11-26.

This interesting paper reports on the identification and characterization of the YmgB protein, a new global modulator of gene expression in Escherichia coli. YmgB protein plays a critical role in biofilm formation and acid-resistance. In spite of the fact that they share only 5% sequence identity, the YmgB 3D structure shows close structural similarity to the Hha protein. Hha has been characterized as a temperature- and osmolarity-dependent modulator of virulence factors in enteric bacteria. Hence, the all-alpha helical structure of these proteins appears to play key modulatory roles in different regulatory networks that enable E. coli and other related bacteria to adapt to a wide variety of environmental imputs. YmgB represents a good example: in some instances, information about the 3D structure of a protein, rather than the primary structure, may lead to the determination of its function.

Evaluated 9 Nov 2007 by Antonio Juarez Gimenez, Faculty of 1000.

5. Autoinducer 2 controls biofilm formation in Escherichia coli through a novel motility quorum-sensing regulator (MqsR, B3022). González Barrios AF, Zuo R, Hashimoto Y, Yang L, Bentley WE, Wood TK, J Bacteriol 2006 Jan 188(1):305-16.

The authors have identified a direct connection between the quorum sensing signal autoinducer-2 (AI-2) and biofilm formation in E. coli. By using synthetic AI-2 and a series of deletion mutants, the authors found that a novel regulatory protein called MqsR regulated biofilm formation. MqsR affected the expression of other regulatory elements that affect biofilm formation, including csrA and QseBC. The authors propose a model for AI-2-mediated biofilm formation in E. coli that can be tested by others. This paper is essential reading for researchers interested in biofilms, quorum sensing, the ecology of the gut and E. coli pathogenesis.

Evaluated 14 Mar 2006 by Eric S. Gilbert, Faculty of 1000.

6. Differential Gene Expression for Investigation of Escherichia coli Biofilm Inhibition by Plant Extract Ursolic Acid. Ren D, Zuo R, González Barrios AF, Bedzyk LA, Eldridge GR, Pasmore ME, Wood TK, Appl Environ Microbiol 2005 Jul 71(7):4022-34

The authors have identified a novel compound that inhibits biofilm formation without inhibiting growth. A library of plant compounds was screened for anti-biofilm activity using a colorimetric assay, and this led to the identification of ursolic acid, which was effective at inhibiting biofilm formation at concentrations as low as 10 ug per mL. A microarray assay of the E. coli transcriptome determined that genes involved in chemotaxis and motility were upregulated by ursolic acid, and genes involved in sulfur metabolism were repressed. Ursolic acid did not influence autoinducer-1 or autoinducer-2 regulated activity. This report will be of great interest to researchers working on all aspects of microbial biofilms, and looks to be an exciting story to follow.

Evaluated 25 Jul 2005 by Eric S. Gilbert, Faculty of 1000.

7. Differential gene expression shows natural brominated furanones interfere with the autoinducer-2 bacterial signaling system of Escherichia coli.
Ren D, Bedzyk LA, Ye RW, Thomas SM, Wood TK, Biotechnol Bioeng 2004 Dec 5 88(5):630-42.

This paper makes a strong statement for the role of autoinducer-2 (AI-2) in the regulation of E. coli gene expression, and the ability of furanone to repress AI-2 controlled genes. Using DNA microarrays, the authors found that nearly 80 percent of E. coli genes that were induced by AI-2 were repressed in the presence of furanone. The authors discuss their work in relation to two previous DNA microarray investigations of AI-2 controlled genes in E. coli conducted by other researchers. The presented work indicates that furanone did not affect gene expression at the transcriptional level, and the authors hypothesize that furanone acts by interacting directly with LuxS. This paper is essential reading for scientists interested in the role of quorum sensing in microbiology.

Evaluated 15 Dec 2004 by Eric S. Gilbert, Faculty of 1000.

8. Magnetic nanofactories: Localized synthesis and delivery of quorum-sensing signaling molecule autoinducer-2 to bacterial cell surfaces. Fernandes R, Tsao CY, Hashimoto Y, Wang L, Wood TK, Payne GF, Bentley WE, Metab Eng 2007 Mar 9(2):228-39.

Fernandes and co-workers demonstrate an exciting new approach to biosynthesis at the cellular scale. The authors took advantage of the pH-dependent features of chitosan-magnetite nanoparticles to conjugate enzymes to novel tyrosine "pro-tags" and then attached the resultant "nanofactories" to the surfaces of living cells for localized small molecule delivery. Moreover, the nanofactory-coated cells could be magnetically captured, allowing for further experimentation. This proof-of-concept work was evaluated using two enzymes that catalyze the production of the quorum-sensing signal molecule AI-2 and AI-2-responsive bioreporter strains. Cells associated with the nanofactories showed a 10-fold increase in activity relative to controls. These researchers are clearly thinking "outside the box" and their nanofactory approach will have relevance to a wide range of biotechnological and medical applications.

Evaluated 7 Feb 2007 by Eric S. Gilbert, Faculty of 1000.

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