Cathelicidins as immunomodulators of host defence against infectious diseases

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

Lung diseases are among the most common causes of ill-heath, accounting for 20% of deaths in the UK, with one third due to infectious diseases. The rise of superbugs is a ever increasing challenge, urgently requiring new treatments and a greater understanding of the body‘s natural protective mechanisms.

Important components of our body‘s early defence system are cationic host-defence peptides (CHDP). Initially studied for their ability to kill bacteria and viruses, we have discovered many ways in which CHDP can alter inflammation, modulating the body‘s response to threat and damage, and the repair systems. CHDP are therefore drug templates with the capacity to kill microbes and enhance our natural protective responses. CHDP also offer the potential to circumvent the strategies that make superbugs resistant to our current conventional treatments.

Building upon the foundation I have established with my recent research, I propose to: 1) determine the cellular pathways involved in the key activities of CHDP (particularly regulating the responses of airway lining cells to infection), 2) determine the role of these activities in protecting against the establishment of infection, and 3) design novel CHDP as potential therapeutics, with a particular focus on the treatment of pathogenic lung viruses, including influenza.

Technical Summary

Respiratory diseases are among the most common causes of morbidity, and account for one in five deaths in the UK, with one third due to acute respiratory infections, influenza or pneumonia. Pathogens resistant to conventional treatments represent an growing challenge. Greater understanding of natural protective mechanisms and novel treatments are urgently required.

Innate responses are the first line of defence, but remain under-researched and under-exploited. Important components of early innate immunity are cationic host-defence peptides (CHDP; e.g., cathelicidins). Initially described as directly microbicidal agents, we have discovered multiple roles for CHDP as modulators of inflammation and immunity; thus, they represent exciting templates for novel therapeutics with the capacity to circumvent existing microbial resistance strategies. Although clearly important in health and disease, their specific roles in defence against infectious diseases remain poorly understood.

The central tenet of this proposal is that the full potential of CHDP-derived antimicrobial therapeutics is only likely to be realised through greater understanding of the multiple mechanisms employed by naturally-occurring CHDP in host defence against specific bacterial and viral infectious diseases.

Building upon the foundation I established during my Research Career Development Fellowship, I intend to address the central hypothesis that cathelicidins are key components of innate host defence against infection, that they mediate a recently-described pro-inflammatory caspase 1-dependent cell death (pyroptosis) of infected epithelial cells, with protective innate and adaptive immune consequences, and that cathelicidins represent promising templates for novel microbicidal immunomodulatory strategies for drug-resistant bacteria and viruses.

I propose to: 1) determine the mechanisms and significance of cathelicidin-mediated pyroptosis of airway epithelial cells infected with invasive bacteria or viruses, and investigate the role of the inflammasome and caspase 1 (including using infection models in vitro and in vivo, live-cell confocal imaging, state-of-the-art in vivo imaging and proteomic analyses); 2) establish the adaptive immune consequences of dendritic cell interaction with infected epithelial cells previously induced to undergo cathelicidin-mediated pyroptosis (including using influenza and Pseudomonas aeruginosa infection models and mutant recombinant virus); and 3) determine the antiviral activities of cathelicidins against respiratory viral pathogens, and the potential for peptide modification in therapeutics (including the use of influenza and respiratory syncytial virus infection models in vitro and in vivo, cryo-electron microscopy and the design of novel CHDP).

This research will elucidate new roles of CHDP in infectious lung disease, and enable development of a novel innate immunity-based strategy with application for viral and bacterial infections at epithelial surfaces.

Publications

10 25 50
 
Description Action Medical Research Grant
Amount £195,625 (GBP)
Funding ID GN2703 
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2021
 
Description Chief Scientist Office Translational Clinical Studies Grant
Amount £299,558 (GBP)
Funding ID TCS/18/02 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 04/2019 
End 03/2021
 
Description Edinburgh Dermatology Research Fund
Amount £3,914 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 09/2015
 
Description Large Grant
Amount £85,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 08/2021
 
Description MRC Public Engagement Festival of Medical Research Award
Amount £3,700 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC Public Engagement Festival of Medical Research Award 2016
Amount £1,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC Public Engagement Festival of Medical Research Award 2018
Amount £1,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC Public Engagement Seed Funding
Amount £3,440 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Telethon-New Children's Hospital Research Fund
Amount $248,730 (AUD)
Organisation Telethon-Perth Children's Hospital Research Fund 
Start  
 
Description CIR - CDC 
Organisation Centers for Disease Control and Prevention (CDC)
Department Influenza Division
Country United States 
Sector Public 
PI Contribution Established anti-influenza properties of cathelicidins in vitro and co-directed in vivo studies which were conducted at CDC Atlanta.
Collaborator Contribution Conducted in vivo studies demonstrating anti-influenza properties of cathelicidins in mice.
Impact Barlow et al 2011 paper in PLoS One. Studies being further developed in my lab.
Start Year 2010
 
Description Collaboration with University of Western Australia 
Organisation University of Western Australia
Department Faculty of Medicine, Dentistry and Health Sciences
Country Australia 
Sector Academic/University 
PI Contribution This collaboration has been advanced and consolidated in 2019 around sample collection from children in Australia for our studies in the UK. We will have developed the hypothesis and raised funding, and will evaluate samples
Collaborator Contribution This collaboration has been consolidated around sample collection from children in Australia for our studies in the UK. Our partners in Australia will collect the samples and provide intellectual input and some analysis.
Impact Publications doi: 10.1371/journal.pone.0117038 Grants Telethon-New Children's Hospital Research Fund 2014 - 2016 T. Strunk, A. J. Currie, D. J. Davidson, O. Levy, D. Burgner, K. Simmer "Antimicrobial proteins and peptides to prevent late-onset sepsis in preterm infants" Value - AUS$248,730.51 (£137,400) Walter Murdoch Distinguished Collaborator award 2012 - 2015 D. J. Davidson, A. J. Currie Value - AUS$30,000 (£19,700) Honours Donald J Davidson Adjunct Associate Professor appointment, Murdoch University, WA, 2018
Start Year 2011
 
Description "Going Viral" SciArt Public Engagement initiative 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact "Going Viral" was a British Society for Immunology funded art-science collaborative programme of work undertaken by 6 artists and 4 immunologists. I was invited to bring my knowledge of immunology to help advise and inspire the artists in this joint exploration of key functions of our immune system.

Going Viral artists produced artworks that consider, question, interpret and present the immunology they have researched. These were launched with the start of the European Congress for Immunology 2012, at the Glasgow Science Centre, who gave a major space to host the exhibition (6th Sept - 21st Oct 2012).
Press coverage: New Scientist
Year(s) Of Engagement Activity 2012
URL https://www.facebook.com/bsigoingviral
 
Description Debating Matters 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact I was a Judge at a regional Rounds of the schools Debating Matters scheme.

n/a
Year(s) Of Engagement Activity 2012,2014
URL http://www.debatingmatters.com
 
Description Edinburgh International Science Festival - Amazing Immunology Cancer Immunotherapy workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The MRC CIR participated at the Edinburgh International Science Festival with a brand new Amazing Immunology workshop

A brand new 'Amazing Immunology' workshop, conceived and developed by Iris Mair, David Taggart, Donald J. Davidson, Ross Mills, Julia Dorin and Marc Vendrell, with additional funding from the British Society for Immunology, was delivered by representatives of the MRC Centre for Inflammation Research at the Edinburgh International Science Festival 2018.

The workshop was a massive success, with an overall attendance of around 80 children (mostly aged 7 to 13) and 30 adults.

The workshop participants learned basic immunology concepts before participating in an activity focused on cancer immunology. They enjoyed a cartoon, puppets, sticker activity and a wildly active new ballpool game; role playing T cells or dendritic cells, fishing for "tumour cells", generating an immune response (with or without "medical interventions") and using their throwing skills to try to destroy the "cancers"!

Excellent feedback was collected at the end of the workshop from adults and children, which is a fantastic reward for the volunteers who ran the activities in these 4 days of fun and science.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/eisf-2018
 
Description Edinburgh International Science Festival 2014 - 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact In 2014, over 2000 visitors came to this drop-in event at the National Museum of Scotland from 15th - 19th April, participating in our new learning activities and discussing science with the volunteers.
In 2015 I ran a sell-out series of workshops for children aged 6 - 11 (120 places) entitled Amazing Immunology
In 2016 we repeated a sell-out series of workshops for children aged 6 - 11 (100 places) entitled Amazing Immunology In 2017 we repeated a sell-out series of workshops for children aged 6 - 11 (80 places) entitled Amazing Immunology

The MRC Centre for Inflammation Research has been asked to contribute to the Edinburgh International Science Festival again in 2015 and to the Midlothian Science Festival in 2015. An article on the event was requested for Immunology News.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/cir-at-edinburgh-in...
 
Description Illustration and development of "MicroMania" an infectious diseases Happy Families card game for school children. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Schools
Results and Impact Development and illustration of an educational scientific children's game about infectious diseases, based on Happy Families.


An educational card game was produced, launched at the British Society for Immunology Congress in December 2011, and now freely available through the BSI. It has been used in a range of public engagement activities and well received by schools.
Year(s) Of Engagement Activity 2011,2012,2013,2014
URL https://www.immunology.org/sslpage.aspx?pid=1844
 
Description MRC Festival of Medical Research 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We develop and new educational games, animations and schools resource on immunology and inflammation and trialled this in 4 schools in the region, with ~ 80 pupils. This provided excellent interaction, new links with schools and invaluable feedback for the next phase of development of this resource.
Year(s) Of Engagement Activity 2016
URL http://www.ed.ac.uk/inflammation-research/information-public/past-public-events/mrc-festival-of-medi...
 
Description MRC Festival of Medical Research 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 24 Teachers trained in using our newly developed Supercytes schools inflammation and immunology resource, which led to teachers signing up to our Supercytes website and receiving the resource pack to use in their teaching.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/supercytes-immune-c...
 
Description MRC Festival of Medical Research 2018: Supercytes Teacher Training 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Developed by medical researchers at the MRC Centre for Inflammation Research at the University of Edinburgh, Supercytes is game-based educational pack designed to introduce immunology and inflammation and a lively and entertaining manner.

The resource features easy, fun, strategic card game; a series cartoons featuring cell immune characters; a dedicated interactive website; quizzes; a competition; a teaching presentation and lesson plan integrated into the Curriculum for Excellence.

The resource pack is freely available to schools in the Edinburgh and Lothians area, and to teachers attending our Supercytes workshops.

This MRC Festival of Medical Research 2018 event was held at the Queen's Medical Research Institute, Edinburgh, on 20 June 2018. It was an interactive workshop to introduce the Supercytes resource to teachers, delivered by researchers Donald J. Davidson, Lisa Kelly and Matthew Burgess, with support from Amy Tyndall and Sheila Marshall.

The event was a great success, with our cohort of 18 Secondary School Science and Primary School teachers learning to use the Supercytes resource, and apparently enjoying playing the game as much as the pupils who have used it!

100% of attendees said that they would definitely use the Supercytes resource, and the group gave a mean rating of 6.8/7 for the quality of the workshop.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/mrc-festival-2018-s...
 
Description National radio, and national newspaper interviews, with additional widespread coverage of press release relating to new publication on Cystic Fibrosis 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An effectively picked up press release on our research paper
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research/information-public/2017-selected-research-summaries/cf-st...
 
Description National television, international & national radio, and national newspaper interviews, with additional widespread coverage of press release relating to new publication on Atopic dermatitis 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Following our press release (detailing our new publication on Atopic dermatitis in Journal of Investigative Dermatology) I was interviewed on the topic for prime time Scottish television news (BBC and STV), international (BBC World service) & national (BBC Five Live, Radio Scotland) radio, and national newspaper (Scotsman), with additional widespread coverage in all the major newspapers in the UK (and many internationally) and news websites. I was also interviewed by a local student newspaper and a specialty patient group website. In addition to widespread dissemination of our research findings, I subsequently had many approaches from patients and their relatives (by phone, e-mail and letter); seeking information and advice and offering to participate in future trials arising from this line of research.
Year(s) Of Engagement Activity 2016
URL https://www.altmetric.com/details/12483351#score
 
Description Primary School outreach visits - Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact I have run a series of self-designed interactive sessions (1 - 3 hours each), on microbiology, immunology and general scientific approaches at East Linton Primary School as a component of their Science weeks, for primary 2 - 6 children.

School asked for further future events and MRC Centre asked to consider broader use of this and other similar events in other schools.
Year(s) Of Engagement Activity 2012,2013,2014
URL http://www.djdavidsonlab.net/cms/?p=1811&paged=4
 
Description Primary School outreach visits - Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I ran a primary school workshop on "Thinking like a scientist" - developing ideas on statistics, reproducible, bias, and scientific approaches with fun activities.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/thinking-like-scien...
 
Description SSERC Teacher training event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact We presenter our new Supercytes Immunology and Inflammation schools resource pack to teachers at this SSREC training day, after which many signed up for the resource to use in their teaching
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/scottish-schools-ed...
 
Description Supercytes Primary School Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Supercytes is a free inflammation biology / immunology resource pack developed at the MRC Centre for Inflammation Research (CIR) for schools, featuring a presentation, a video about the CIR, cell cartoon characters, worksheets, quizzes, a strategic card game and a dedicated website (see links below).

The pupils at East Linton Primary School were highly participatory and loved playing the game. They doubled their overall class score when the quiz was taken after the activity (compared to the pre-activity scores on the same quiz); 16/25 got a question about the difference between adaptive and innate immunity correct after the activity, 17/25 got the signs of inflammation right, and an astonishing 11/25 (up from 1/25 before the activity) correctly identified the main specialist functions of a neutrophil (which meant knowing to exclude "immune memory" from the list)!

Feedback was very positive; they loved the cartoons and found that this helped them understand better, they thought the card game was "brilliant", found the video about our Centre (and finding out what people do there) very informative and interesting, and "enjoyed hearing the 'big' words"!
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/inflammation-research/information-public/past-public-events/supercytes-primary-...
 
Description Supercytes Resource and website launch 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Initial limited trial launch of Supersytes - our new school's resource on immunology & Inflammation; featuring card game, animations, teaching lesson plans, worksheets, quiz, competitions and interactive website. Schools are signing up and using the resource in the class teaching.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/inflammation-research/information-public/resources/supercytes
 
Description Supercytes Teacher Training in Selkirk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact CIR researchers ran an interactive workshop to train Borders Biology teachers how to use our "Supercytes" game-based schools' resource, focused on immunology and inflammation.

"Supercytes - the immune cell standoff" is a new free resource for schools.

Developed by medical researchers at the MRC Centre for Inflammation Research at the University of Edinburgh, this is game-based educational pack designed to introduce immunology and inflammation and a lively and entertaining manner.

Using different gaming formats for students aged 9-18, it introduces younger learners to white blood cells and how our bodies fight infection, and supports older students learning basic immunology and inflammation biology. The resource features an easy, fun, strategic card game, a series of cartoons featuring cell immune characters, a dedicated interactive website, quizzes, a competition, a teaching presentation, and a lesson plan integrated into the Curriculum for Excellence.

The resource pack is freely available to schools in the Edinburgh and Lothians area, and to teachers attending our Supercytes workshops.

CIR Researchers Donald J. Davidson, Filipa Henderson Sousa and Francesco Vacca travelled to the Selkirk to run an interactive workshop, introducing the Supercytes resource to 26 Biology teachers from various Borders schools, as a component of their in-service training event at Selkirk High School.

It was a most enjoyable and lively workshop, with the teachers quickly grasping the game concept and participating most enthusiastically! The feedback was really positive, with 100% of attendees saying that they would definitely use the Supercytes resource, and we look forward to supplying the resources for this cohort to use with their classes.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/inflammation-research/information-public/public-engagement-news/2018/supercytes...