Teasing out the mechanisms of biofilm formation for the treatment of S. aureus infections on indwelling devices: the role of the surface protein SdrC

Antibiotic resistance has become a great challenge in the healthcare setting. In particular antibiotic resistant strains of Staphylococcus aureus pose further challenges. Methicillin resistant S. aureus (MRSA) is widespread in healthcare facilities and in the wider community and multi-drug resistant strains have been identified. S. aureus is normally present on the surface of the skin where it causes no harm. However, it can easily colonize open wounds causing infection. Systemic infections can result from these wound infections leading to severe problems such as sepsis and infective endocarditis. Infection after surgical implantation of devices, such as joint replacements, can result in the formation of biofilms coating the devices that are difficult to treat. Biofilms are an accumulation of bacteria on a surface which often persist as most antibiotics do not easily penetrate them. In biofilms, bacteria interact directly with the foreign surface, with host proteins coating the surface and can also accumulate through interactions directly with each other.

Thus, there are multiple mechanisms involved in biofilm formation. It is important to fully understand all the mechanisms of biofilm formation in order to be able to disrupt their formation and persistence. In our recent paper, we have characterized the direct binding interaction (cell-cell adhesion) through the S. aureus surface protein, serine-aspartate repeat protein C (SdrC). Our study also reveals the mechanism of interaction between SdrC and inert surfaces. Furthermore, we have demonstrated how a small peptide can be used to block these interactions preventing biofilm formation suggesting a possible approach that could be used to treat SdrC dependent S. aureus biofilms. This study is the result of a multi-disciplinary collaboration across research institutes in Ireland and Belgium with Dr. Brennan (RCSI) contributing to the molecular modelling, Prof. Joan Geoghegan, Prof. Timothy Foster and Leanne Hayes (Trinity College Dublin) leading the molecular biology and microbiological functional studies and researchers from University Catholique de Louvain characterizing the interactions quantitatively using atomic force microscopy.

Marian Brennan

More details can be found in “Molecular interactions and inhibition of the staphylococcal biofilm-forming protein SdrC”.

 

International Research and Education

Prof Tracy Robson (MCT), Prof Jochen Prehn (Physiology & Medical Physics) and Dr Darran O’Connor (MCT) have recently returned from 1 week at the College of Pharmaceutical Sciences, Soochow University, Suzhou, China where they participated in a workshop with faculty to explore research collaborations and future joint funding applications under the newly announced SFI-NSF Partnerships for International Research and Education. Supported by an Erasmus+ programme coordinated by Prof Marc Devocelle (Department of Pharmaceutical and Medicinal Chemistry), the workshop involved presentations from RCSI and Soochow investigators describing their work and discussion to identify areas of synergy. Afternoon lectures by RCSI faculty were opened to postgraduate and postdoctoral researchers from Soochow, leading to a vigorous and stimulating discussion and Prof Xinliang Mao from Soochow will visit RCSI next month to further strengthen future collaborative research opportunities. 

Left to Right: Prof Tracy Robson (MCT), Prof Jochen Prehn (Physiology & Medical Physics) and Dr Darran O’Connor (MCT)

At the invitation of the President of the British Pharmacological Society, Professor John Waddington (Emeritus, RCSI) has been elected to Fellowship of the Society; this is in recognition of his career contributions to research, education and service in the discipline of pharmacology, not just in Ireland but globally. He has recently returned from 3 weeks at the College of Pharmaceutical Sciences, Soochow University, China, under his joint appointment as a Professor of Pharmacology. While there, he continued collaborative research, gave undergraduate lectures and fostered further joint endeavours between RCSI and Soochow University, which is in the top 5% of Chinese research universities.   

Tracy Robson

MCT Awards at Research Day 2017

Dear all,

MCT was well represented in the award ceremony at the recent Research Day; our congratulations go to the following:

Dr Mark McCormack, for receiving prizes in the RCSI Author Citations Prizes in two categories – the 2011 Most Highly Cited RCSI Senior Authored Paper and the 2011-2015 Most Highly Cited RCSI Senior Authored Paper with International Collaboration – for his paper entitled “HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans” published in the New England Journal of Medicine.

Dr Cathy Wyse, as part of Dr Annie Curtis’s group, was presented a prize for the front cover illustration of the RCSI Research Day abstract book, for a striking image of glial cells at the junction between the brain and pituitary gland.

Tony McHale, PhD student at the School of Pharmacy, & MCT, and the Irish Centre for Vascular Biology, RCSI received the prize for the best postgraduate oral presentation, for his talk on the topic of “First in Class Potential Novel Drug for the Treatment of Sepsis Caused by Urinary Tract Infections”.

Medical student Jack Donohue [RSS student], was awarded the Dr Harry O’Flanagan Prize for Excellence in Undergraduate Research for the best undergraduate oral presentation for a project carried out as part of the RCSI Research Summer School entitled “Sanger Confirmation of Suspected Epilepsy-Related Pathogenic Variants Identified Through Next-Generation Sequencing”.

Very well done to all!

Tracy Robson

Diagnostic gene sequencing in adults with epilepsy and intellectual disability

MCT Research Talks – 20th February 2017

Sinead Heavin reports

Sinead Heavin, PhD Post-Doctoral Researcher

Epilepsy is a common neurological disorder that affects ~40,000 people in Ireland. There are many different types of seizures which are caused by uncontrolled electrical impulses in the brain. Anti-epileptic drugs control seizures for ~50% of people with epilepsy but up to ~30% of patients remain uncontrolled despite treatment with multiple drugs. Epilepsy is caused by a number of factors include stroke, trauma and infections. However, more recently we have learned that epilepsy can be caused by genetic mutations. Some epilepsies are heritable while others arise de-novo. Many patients with an intellectual disability (ID) also have epilepsy. Many of these patients lack a specific diagnosis due to limited testing and available investigations. We sequenced a cohort of 99 adult patients with epilepsy and ID on a custom gene panel of ~150 genes. A likely pathogenic variant was identified in 20 patients in 19 different genes, including SCN1A, DCX and DEPDC5, well-known epilepsy genes. Furthermore, we identified copy number variants in two patients which are likely causative. Further work is needed to investigate the phenotype-genotype correlations identified in this study and any potential treatment options that may arise.

Kay McKeon

8 February 2017

An informal, private reception was held in the College for Kay McKeon on Wednesday, 8th February, to mark her retirement and contribution to RCSI after 39 years.

Kay joined Clinical Pharmacology in 1978 and with Prof. Kevin O’Malley was responsible for commissioning the then ‘new’ laboratories. She continued to play a fundamental role in developing Clinical Pharmacology’s laboratories and building the department’s reputation through the 1980s and 1990s into RCSI’s premier research department.

She played a central role in assisting Kevin O’Malley’s successor, Prof. Des Fitzgerald, in securing RCSI’s first large HEA-PRTLI and SFI grants, working long hours with the intricate details and logistics for such applications.

During this period, Kay was seconded to oversee the development of the RCSI Centre for Human Proteomics, before returning to base and seeing in another period of change on the departure of Prof. Fitzgerald and formation of Molecular & Cellular Therapeutics (MCT) from the Departments of Biochemistry and Clinical Pharmacology under Profs. David Croke and John Waddington as HODs; she played a key role in the management of MCT as a member of it’s Executive.

At a more personal level, Kay was someone who carried out her responsibilities in a genuinely supportive and politically astute manner; many appreciated her sensitivity, in assisting all ‘new staff’ settle in and in maintained balance and stability in overseeing laboratories with up to 100 staff.

Yet in addition to this, Kay also found the time to contribute more broadly to RCSI, particularly its philanthropic activities, for example, the Old Folks Christmas Lunch for those living in the vicinity of the College and related activities; an all-too-rare rare combination of professionalism and altruism.

An important part of what Clinical Pharmacology and MCT has achieved serves as her legacy to the College, in making MCT what it is today and the entity that Prof. Tracy Robson has recently inherited.

Hebrews 6 (10 … 19): ‘For God would not be so unjust as to forget all that you did for love of his name, when you rendered service to his people, as you still do … It is like an anchor for our lives, an anchor safe and sure’.

Kay has been an ‘anchor safe and sure’ across four decades. We thank you, Kay, for everything you’ve done for Clinical Pharmacology, MCT, RCSI and the community at large and wish you well for the future.

miR-155, a master regulator of the immune response

MCT Research Talks – 13th February 2017

Dr. Claire McCoy

Background

I have recently arrived as a Lecturer in Biochemistry/Immunology within the Molecular and Cellular Therapeutics Department at RSCI. I am a dedicated and passionate Biochemist/Immunologist who obtained a BA (Mod) in Biochemistry from Trinity College Dublin in 2001.

Dr Claire McCoy

In 2006, I completed my PhD at the University of Dundee, Scotland after which I conducted my postdoctoral training in innate immunology with Prof Luke O’Neill. In 2010, I received a Marie Curie Mobility Fellowship where I gained scientific independence and re-located to the Hudson Institute of Medical Research in Melbourne, Australia. In 2014, I was awarded an Australian NHMRC project grant enabling me to lead an independent research team, conducting my research specifically on the regulation of microRNAs in innate immune cells, with a particular focus on inflammatory diseases such as Multiple Sclerosis.

Specific Research
My lab aims to understand how microRNAs regulate inflammation in disease. Our particular focus is how the pro-inflammatory microRNA, miR-155, plays a fundamental role in one immune cell subset called the macrophage. Macrophages are the sentinel cells of our immune system and quickly respond to infection to clear invading microbes. However, in chronic inflammatory diseases and autoimmunity, the presence of macrophages largely contributes to the damage, tissue destruction and symptoms associated with these diseases. Our research has shown that miR-155 is a key driver of this response. My lab aims to identify the molecular and functional mechanisms that underpin inflammatory macrophages, with the aim that miR-155 inhibition will lead to real therapeutic potential.
Multiple Sclerosis (MS) is a progressive degenerative disease where the prevalence in Ireland far exceeds the global average. Disease onset occurs between 20-40 years, an age critically affecting working and family life. To this day, there is no known cause and no cure for MS. Although, the early disease can be managed by current drug therapies, there is no treatment at the later progressive stages of disease, and no known treatments to repair the damage caused to the central nervous system. My research aims to uncover the role of macrophages in MS, and the contribution of miR-155 in this effect.

Awards
Claire McCoy is the recipient of a prestigious Marie Curie International fellowship and an Investigator Project Grant from the National Health and Medical Research Council (NHMRC), Australia. Altogether my research has attracted €800K in both national and international funding. I have published >21 highly cited and seminal publications in Nature Reviews Immunology, Nucleic Acids Research, Journal of Leukocyte Biology and Journal of Biological Chemistry. I am book editor for Springer Science, USA, as well as peer reviewer for international journals and funding agencies.

I will be talking about my research at 12pm TR4, Monday 13th Feb. The title of my talk will be ‘miR-155, a master regulator of the immune response’.

ALL WELCOME!

Dr. Claire McCoy

Lecturer in Biochemistry/Immunology,
Royal College of Surgeons in Ireland,
123 St Stephens Green,
Dublin 2,
Ireland.
Tel: 01-4025017
Email: clairemccoy@rcsi.ie

The Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI

MCT Research Talks – 30th January 2017

Last week’s departmental talks encompassed a Deep Dive into Clock biology in Macrophages affecting the Inflammatory Response. This area is the focus of the Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI.

Jamie Early, my PhD student

Jamie Early (PhD student of the Curtis Lab) currently residing in the Luke O’Neill Laboratory presented his findings on the role of the circadian clock in suppressing inflammation in macrophages and if the anti-oxidant transcription factor and redox sensor NRF2 plays a role. His talk was titled ‘The macrophage clock is a key controller of the anti-oxidant and inflammatory response via the transcription factor Nrf2’.

Second up, we had Mariana Cervantes (PhD student and visiting scientist from the Instituto Politecnico Nacional (IPN) in Mexico) present her talk titled ‘The macrophage clock is having a profound impact on mitochondrial dynamics- what are the implications for inflammation?’

Mariana Cervantes

Mariana is interested in how mitochondria alter their morphology, either fusing together to form networks or fragmenting into smaller units termed fission. She is trying to uncover if the clock is regulating this process and if so what are the implications for the inflammatory response.

This work is part of a collaboration between RCSI and  Luke O’Neill laboratory at TCD and is funded through Science Foundation Ireland

A pharmacogenomic exploration of adverse drug reactions in epilepsy (PGXOME)

For most people with epilepsy, long term treatment with anti-epileptic drugs (AEDs) are necessary to prevent the seizure, and 40% do not respond to the first line of AED, leading to an often lifelong odyssey of trial and error towards effective treatment that is often not found. Epilepsy is primarily treated using AEDs, but these are associated with a considerable risk for adverse drug reactions (ADRs), some of which have been shown to have a genetic predisposition. For example, the genetic variant HLA-A*3101 is a common risk factor for rash and severe blistering skin reactions with the drug carbamazepine (Tegretol) in Europeans. However there are few other predictors of some more common ADRs.

Dr. Mark McCormack

The EpiPGX Consortium was established to identify genetic biomarkers of epilepsy treatment response from patient centres across Europe. The EpiPGX Consortium has generated genetic profiles on over 8000 patients with matching detailed drug response and medical histories. In order to investigate the links between genetic profiles and ADRs in epilepsy, Dr. Mark McCormack will travel to UMC Utrecht, the Netherlands for one year on a  Marie-Skłodowska-Curie Fellowship from the European Commission.

The aim of this fellowship is to identify clinically useful genetic variants to predict adverse reactions to AEDs. This will help optimize personalized treatment, limit the trial and error approach of AED choice, and thus improve medication safety and quality of life in epilepsy.

RDS Primary Science Fair

Dr. Maria Morgan reports

On the 12th January 2017 I had the pleasure of attending the RDS Primary Science Fair which runs alongside the BT Young Scientist and Technology Exhibition. Although given the title of ‘Head Judge’ the Fair is non-competitive and provides a platform for showcasing STEM investigations (science, technology, engineering and maths) undertaken by primary school classes across Ireland.

Judges briefing at the RDS Primary Science Fair

Children exhibited their whole-class projects which included topics ranging from ‘How can we assist the declining bee population in our local area?’ to ‘Ambidextrous! Can I train my other hand?’. One of my favourites was ‘Why do we like Pink Lady apples so much?’ which demonstrated higher levels of sugar in Pink Ladies compared to other apple varieties. At another stand I was given the opportunity to have my lung capacity measured using a 5L water cooler bottle and some garden tubing (well how could I say no!). It’s such a privilege to attend the Fair each year where the positivity and enthusiasm for science means you come away with a feel-good scientific glow and a reassurance that the future of STEM in Ireland is in excellent little hands!
For more information on the RDS Primary Science Fair go to: www.rds.ie/Ireland-s-Philanthropic-Society/Our-Work/Projects/RDS-Primary-Science-Fair#sthash.z8tSvgG1.dpuf