Team:Dundee

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     <h1 style="color: #FFFFFF;">Dundee University</h1>
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                <li><a href='https://2012.igem.org/Team:Dundee/Team'><span>Team Members</span></a></li>
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      <li class='has-sub'><a href='https://2012.igem.org/Team:Dundee/Project'><span>Project</span></a>
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              <li><a href='https://2012.igem.org/Team:Dundee/Project'><span>The Problem</span></a></li>
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<li class='has-sub'><a href='https://2012.igem.org/Team:Dundee/Strategy'><span>Wet Lab</span></a>
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            <a href="https://2012.igem.org/Team:Dundee/Parts">Parts</a>
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             <a href="https://2012.igem.org/Team:Dundee/Notebook">Notebook</a>
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            <a href="https://2012.igem.org/Team:Dundee/Safety">Safety</a>
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        <h2><img src="https://static.igem.org/mediawiki/2012/f/fb/Abstract.png"></h2>
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<b>Six, Lyse and Obliterate: a synthetic silver bullet against healthcare acquired infection.</b><br>
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Hospital acquired infections are a global problem. One example is <I>Clostridium difficile</I>, a bacterial pathogen that infects patients undergoing prolonged antibiotic treatment and results in pseudomembranous colitis, a potentially fatal gut infection. This project aimed to design a synthetic bacterium that would respond to <I>C. difficile</I> infection and kill the pathogen <i>in situ</i>. <I>Escherichia coli</I> was engineered to secrete an endolysin from a bacteriophage that would specifically attack the <I>C. difficile</I> cell wall. The endolysin was fused to the extracellular components of an engineered Type VI Secretion System from <i>Salmonella</i>, which itself comprised 13 different proteins. In addition, a synthetic ‘inflammation biosensor’ was developed, based on a two-component system from <i>Salmonella</i>, with the aim of restricting endolysin secretion to the diseased colon only. Mathematical modelling was used to assist in the development of the laboratory work and to investigate potential therapeutic strategies beyond the scope of the experimental programme.
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        Micrograph depicting Gram-positive <em>C. diff</em> bacteria using a .1µm filter.<br />
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        Public Domain : Obtained from CDC image library (http://phil.cdc.gov)
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        <center><h2>Clostridium Difficile</h2></center>
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        <em>Clostridium difficile (C. diff)</em> is a gram- positive bacterium that lives naturally in the gut. In healthy individuals, the levels of <em>C. diff</em> are kept constant as it is outcompeted by other species in the gut flora. However, when patients receive large doses of antibiotics, competing gut flora can be wiped out. This can allow numbers of <em>C. diff</em> to increase to a level where infection can be caused, resulting in severe colitis. <em>C. diff</em> has therefore become a major cause of hospital acquired infections, with, for example, some 2645 patients in hospitals in England and Wales found suffering from <em>C. diff</em> induced colitis in March- May 2010. Infection rates have also been high at Dundee's Ninewells Hospital, which is affiliated with the University of Dundee, and so for us, this is also a very local health problem. Up until now, there have been two ways of treating this problem: prescribe more antibiotics, with the added difficulty of possibly causing more resistance to build-up, or by means of faecal transplant. A faecal transplant involved the faeces of another person being transplanted directly into the patient's colon or through a drip into the stomach. This has been proven to be effective in test cases, but is obviously an unsavoury form of treatment for many patients and so the idea of creating an alternative gave rise to this project.
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         <center><h2>Type VI Secretion System</h2></center>
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        Many bacterial species have evolved secretion systems Type VI secretion systems are naturally found in gram negative organisms, including <em>Serratia</em> species, <em>Vibrio cholerae</em> and <em>Pseudomonas aeruginosa</em>, but a putative type VI system has also been found in <em>Salmonella typhimurium</em>, which is closely related to <em>Escherichia coli (E. coli)</em>.  The proteins for <em>Salmonella</em> type VI secretion systems are encoded by more than 13 genes, including Hcp, which encodes for the main feature of the system, the needle. This projects through the periplasm and outer membrane, secreting effector molecules, via the tip protein which is encoded by the gene VgrG. Hcp and VgrG are largely conserved across all species expressing these systems.  The secreted effector molecules are thought to play a role in the pathogenesis of higher organisms and could help facilitate interactions with other bacteria. 
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        <center><h2>Project Summary</h2></center>
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        The aim of our project is to create a new type of synthetic <em>E. coli</em>, expressing a simplified type VI secretion system that will secrete a <em>C. diff</em> specific effector, endolysin. It is hoped that the needle will either be able to puncture the <em>C. diff</em> cells and secrete the endolysin directly into the organism or that the endolysin will come into contact with the <em>C. diff</em> cell surface after secretion. We hope to prove that the new strain of <em>E. coli</em> will be able to produce enough needles on the cell surface which can then come into contact with <em>C. diff</em> cells and that enough endolysin is secreted to kill them, so in vitro experiments will be carried out to test this hypothesis. Experiments will also be set up that show that our strain of <em>E. coli</em> is able to out-compete <em>C. diff</em>, resulting in reduced numbers of the bacterium and so less chance of infection.
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        <center><h2>Mathematical Modelling</h2></center>
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        The depth and range of the mathematical modelling will evolve throughout this project, from models of growth for <em>Salmonella</em> and the strain of <em>E.Coli</em> that we will engineer, to systems ordinary and partial differential equations that will show us not only how two populations interact, but how the shape and natural processes of the colon affect this interaction.
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Other aspects that we will look at modelling are the number of  "needles" that we can engineer the <em>E.Coli</em> to create and the amount of endolysin that must be secreted to lyse all of the <em>C.diff</em> bacteria. Using software such as MATLAB&#174; and COMSOL&#174; we are able to create visual representations of population interactions such as graphs and animations of the colon as we introduce the <em>E.Coli</em> to lyse the excessive levels of <em>C.Diff</em>.
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        <center><h2>Software Development</h2></center>
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      Beyond the team's Wiki and blog site, ongoing work is taking place to develop an Android based application framework. It shall encompass any tools that the team finds useful, and will be released at the end of the project so that it may be utilised as a starting point for other similar projects.
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The team is also working on a desktop modelling tool that utilises the principles of cellular automata to graphically illustrate the cell interactions that are taking place between the modified <em>E.Coli</em> and <em>C.Diff</em> cells. The application currently models cell mytosis, cell movement, cell lysis and flow. Work on the application is continuing to encompass further aspects such as available nutrition, control over colony sizes and initial placement of cells within the model. The completed application, including source code, will be released for Windows and Linux development environments so it may be used by others in the future for practical as well as educational purposes.
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Latest revision as of 21:03, 26 September 2012


Six, Lyse and Obliterate: a synthetic silver bullet against healthcare acquired infection.
Hospital acquired infections are a global problem. One example is Clostridium difficile, a bacterial pathogen that infects patients undergoing prolonged antibiotic treatment and results in pseudomembranous colitis, a potentially fatal gut infection. This project aimed to design a synthetic bacterium that would respond to C. difficile infection and kill the pathogen in situ. Escherichia coli was engineered to secrete an endolysin from a bacteriophage that would specifically attack the C. difficile cell wall. The endolysin was fused to the extracellular components of an engineered Type VI Secretion System from Salmonella, which itself comprised 13 different proteins. In addition, a synthetic ‘inflammation biosensor’ was developed, based on a two-component system from Salmonella, with the aim of restricting endolysin secretion to the diseased colon only. Mathematical modelling was used to assist in the development of the laboratory work and to investigate potential therapeutic strategies beyond the scope of the experimental programme.




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