Investigation of the molecular and cellular mechanisms of in vitro phage therapy in human cells and of the innate immune response against E. coli O18

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

The problem of antimicrobial resistance is nowadays major and the need to identify alternative methods to antibiotics to tackle bacterial pathogens is obvious. One of the potential alternatives is phage therapy, the use of bacteriophages with high specificity against the targeted pathogen, as antimicrobial agents. Even though the interest in phage therapy has grown lately due to the problem of antimicrobial resistance, there are still concerns of this approach among others because of the potential for immune responses and rapid toxin release upon bacterial lysis. In this project, we aim to investigate the cellular mechanisms of phage therapy in vitro, using infected human cell line models mimicking the disease caused by the pathogen of interest, and further identify ways to measure the innate immune response in human cell environment against the targeted pathogen and the phage. Additionally, we will construct different phages with optimized characteristics compared to the wild type to be used in human cell environment and we will compare the immune response using different conditions and the different phages. Our aim is to investigate the conditions in which the immune response against phages is minimal. These results will help us investigate better the basic mechanisms of phage therapy and how it can be made safer.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1786881 Studentship BB/M01116X/1 03/10/2016 29/05/2021 Christian Moller-Olsen
 
Description We have examined the molecular and cellular mechanisms of in vitro phage therapy in human cells. We found that the phages enter urinary epithelial- and cerebral endothelial cells by constitutive phagocytosis, that they can effectively infect and kill intracellular bacteria, and that they are degraded by TLR-dependent LC3-assisted phagocytosis. In these two different cell systems, phages were shown not to activate selective autophagy. Further analysis showed that phages do not influence the relative expression levels of inflammatory markers of cerebral endothelial cells, while the barrier function of cerebral endothelial cells is potentially temporarily decreased by the addition of phages.
Exploitation Route As with most novel research, once you answer one question you find that you have set yourself two new ones. The first half of the research is published and the second half is under review. The contribution made in this study has the potential to make a substantial impact on the continued development of phage therapy, demonstrating the in vitro efficiency and safety.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Participation and oral presentation at the MIBTP Student Symposium, Leicester. April 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact I presented a short talk about my PhD research and engaged with fellow PhD students.
Year(s) Of Engagement Activity 2019
 
Description Participation and oral presentation at the Microbiology Society Annual Conference, Belfast. April 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I presented a talk about my research from the first 18 month of my PhD. I also had had the opportunity to discuss my data with peers and meet new potential collaborators.
Year(s) Of Engagement Activity 2019
URL https://doi.org/10.1099/acmi.ac2019.po0490
 
Description Participation and oral/poster presentation at the FEBS Advanced Biosystem Design, Spetses, Greece. September 2019. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was a 8-day workshop arranged by WISB (Warwick, UK) and Synmikro (Marburg, Germany) that attracted leading scientists in synthetic biology and bioengineering and international PG students and early career researchers. I presented a poster during the workshop and on the basis of this was selected to give a talk. This workshop gave me the opportunity to discuss research data and challenges with peers. Also, being in Greece, it was a very informal environment encouraging conversation.
Year(s) Of Engagement Activity 2019
 
Description Participation and oral/poster presentation at the Medical Research Foundation AMR Conference & Workshop, Bristol. August 2019. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact This was a brilliant week in AMR arranged by the MRF. It consisted of a two-day conference with 300 AMR researchers from around the country where I presented a short talk and a poster. This was followed by a three-day residential workshop with the 2018-2019 AMR cohort. The interesting thing about this workshop was that we were given a task within AMR but outside our own field. During the workshop, my group was working with AMR in the environment and visited a sewage plant to discuss the release of AMR drivers during storming events and daily operation.
All in all, this week gave me the chance to learn about all the diverse research being done in AMR and meet leading scientists in all areas of AMR.
Year(s) Of Engagement Activity 2019
 
Description Participation and poster presentation at Biochemical Society Conference, Warwick. December 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I participated in this conference and presented a poster entitled "Improving bacteriophages for therapeutic use".
Year(s) Of Engagement Activity 2019
 
Description Participation and poster presentation at SLS PGR Symposium, Warwick. March 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact I presented a poster at this symposium and was awarded a "top five" poster prize. My poster was entitled "Molecular and cellular mechanisms of in vitro phage therapy".
Year(s) Of Engagement Activity 2019
 
Description Participation in World Antibiotic Awareness Week, Warwick. November 2019. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I and others presented posters at University House, Warwick University, detailing the varied AMR research performed at the School of Life Sciences. The idea was to engage with the University management and educate about AMR.
Year(s) Of Engagement Activity 2019
 
Description Science on the Hill - AMR. December 2019. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact My Supervisor, Antonia Sagona, gave a talk about the use of phage therapy to target antibiotic-resistant bacteria. I and other members of the lab group engaged with the general public and presented various bacteria/phage on culture plates and microscopes.
I am always interested in engaging with the general public as it gives me a chance to present my research in a different way and often leads to interesting questions and discussions.
Year(s) Of Engagement Activity 2019