Lab-of-the-month for July 2014: Gary Entrican, Moredun Research Institute

Professor Gary Entrican is a Principal Research Scientist at the Moredun Research Institute, based at the Pentland Science Park at Easter Bush, where the focus of work in his group is to understand the pathogenesis of Chlamydia in sheep and humans

Gary holds an Honorary Professorships at both the Universities of Edinburgh and Glasgow.  He studied Immunology at the University of Glasgow before joining the Moredun Research Institute in 1986, where he began his work on immune regulation in sheep.  He works with a talented team of postdocs and PhD students at Moredun, and has several very fruitful collaborations with external researchers.

Understanding chlamydial infection and reproductive failure in sheep

Gary's current research interests are the cytokine biology and cellular immunology of sheep and cattle.  In particular he focuses on the pathogenesis of chlamydial infections, and the resulting reproductive failure and abortion in these ruminants.

Gary gave an excellent presentation about his work at the Edinburgh Infectious Diseases symposium on 21 May 2014, in the Royal College of Physicians, Edinburgh, which you can watch below.

More about Chlamydia abortus

Chlamydia abortus is the single most common diagnosed cause of infectious abortion in sheep flocks, accounting for almost 50% of reported cases of abortion/stillbirths in the UK each year. This reduces agricultural efficiency and productivity and can have a major negative financial impact for sheep farmers as abortions storms can result in lamb losses in excess of 30% in a season. C. abortus is a zoonotic pathogen and it is very important that pregnant women take precautions to avoid contact with sheep, especially at lambing time as infection will not only cause abortion but is potentially fatal for the mother.

There are several barriers to effective management of chlamydial abortion in sheep, most notably an inability to effectively diagnose persistently-infected sheep before they abort. The current vaccine is live-attenuated and is sub-optimal. Moreover, vaccinated sheep cannot be discriminated from those that have aborted using serologically-based assays. This complicates the introduction of replacement breeding ewes into flocks that are free of Chlamydia. A very important feature of chlamydial abortion is that sheep develop protective immunity after abortion. A major research thrust is understand the mechanisms of disease pathogenesis and identify the immunological correlates of protection that can be mimicked by a new, subunit vaccine. As for all veterinary species, there are relatively few reagents to analyse immune responses in sheep compared to mouse and human. Therefore, a major thrust of our work has been to develop and evaluate immunological reagents for sheep (and cattle).

The persistence of C. abortus in sheep is directly related to its biphasic obligate intracellular developmental cycle, a feature it shares with all chlamydial species. Consequently the growth of Chlamydia and the ability to conduct experimental infections in vitro and in vivo is highly specialised. The expertise on Chlamydia at Moredun has therefore been the basis of highly fruitful collaborations with University of Edinburgh on human chlamydial infections, most notably C. pneumoniae and C. trachomatis with Sarah Howie and Andrew Horne in the Queen's Medical Research Institute at Little France. 

Research in a Nutshell

Gary has also made a Research in a Nutshell video where he summarises the research focus of his lab in just a minute!

Main projects currently running in the lab

1. Investigation of innate and adaptive immune responses to Chlamydia abortus infection for implementation of disease prevention and control.

The aim of this project is to investigate the host-pathogen interactions during C. abortus infection in sheep with a view to understanding disease pathogenesis and the mechanisms of protective immunity. This work is conducted as part of the Scottish Government Rural and Environment Science and Analytical Services Division (RESAS) funded Programme at Moredun (2011-16). This includes the cells and cytokines associated with infection and recall responses and is conducted with Sean Wattegedera and Mara Rocchi. The cellular work has been supported by a number of students and visiting workers, including Stefano Guido.  This project is integrated with the chlamydial vaccine and diagnostic work at Moredun which is led by David Longbottom. The project also involves a component of improving our capability to conduct ruminant immunology research through reagent development and evaluation. Moredun currently holds the most extensive portfolio of functionally-active recombinant sheep cytokines. This work has been a very important platform for attracting other research funding as described below.     

Lab photo taken in summer 2013 L to R:  Laura Doull, Sean Wattegedera, Mara Rocchi, Gary Entrican, Yvonne Pang and Stefano Guido

2. The route to identification of immune correlates of protection in ruminants.

The aim of this work is improve our capability to study cellular immunity in cattle and sheep  to underpin strategic approaches to vaccine design.  Working in collaboration with colleagues Sean Wattegedera and Colin McInnes at Moredun, and Liz Glass and Jayne Hope at the Roslin Institute, the project studies the function of T helper cell subsets and monocyte/macrophage subsets during immune activation in cattle and sheep. The aim is to provide the capability to identify immunological correlates of protection in sheep and cattle and ultimately to accelerate vaccine development.

The project is funded by a grant of £935,000 from the BBSRC with the support of the Scottish Government Rural and Environment Science and Analytical Services Division (RESAS).  The grant is also supported by an Industrial Partner AbD Serotec, a leading commercial supplier of veterinary immunological reagents.  This invovlement with industry is a crucial feature of the work, allowing rapid translation of the work in the lab, into reagents which can be used by the global ruminant immunology research community.  The project emloys a PDRA at Roslin (Yolanda Corripio-Miyar) and a Research Scientist at Moredun (Yvonne Pang).

PhD student projects

Gary also supervises several PhD students who either work directly with him or with collaborators in Edinburgh and Glasgow.

  • Carly Hamilton:  Neonatal vaccination: role for innate immune cell interactions in BCG vaccination (2012-15). BBSRC/Zoetis CASE PhD Studentship collaborating with Jayne Hope at the Roslin Institute which seeks to understand the role of NK cells in the elevated responses to BCG that are observed in young calves compared to older cattle.   

  • Laura Doull:  Inflammasome activation in ruminant cells infected with Chlamydia abortus 2011-15). BBSRC/Zoetis CASE PhD Studentship collaborating with Liz Glass at the Roslin Institute to investigate and compare the innate immune responses of sheep and cattle to C. abortus as infection in sheep results in abortion whereas in cattle it does not.

  • Eleonora Melzi:  The Role of Dendritic Cells in the Pathogenesis of Bluetongue (2012-15). This project is the WB Studentship, awarded by Moredun and University of Glasgow. The aim is to compare the interactions bluetongue virus of low- and high-pathogenicity with sheep dendritic cells to gain a better understanding of how the virus causes disease and potentially influences the development of adaptive immunity. Eleonora is supervised by Massimo Palmarini at the University of Glasgow and Mara Rocchi at Moredun.

  • Rebecca McLean:  Activation of immune responses using ovine lentivirus vaccine vectors (2013-2016). Moredun Scientific PhD Studentship led by David Griffiths (Moredun) and collaborating with Jayne Hope at the Roslin Institute. The aim of the project is to develop lentiviral constructs that lend themselves to vaccine delivery in sheep and investigate how these constructs elicit innate and adaptive immune responses. 

  • Sevasti Giakoumelou:  Does Chlamydia trachomatis infection have a causative role in miscarriage (2012-15)?  This PhD project is supported by University of Edinburgh and Tommy's charity and is led by Andrew Horne at the Centre for Reproductive Health and in conjunction with Sarah Howie at the Centre for Inflammation Research in the Queen’s Medical Research Institute at Little France and Nick Wheelhouse at Moredun. The aim is to investigate the clinical association between C. trachomatis and reproductive failure in humans, supported by mechanistic studies on infected human stromal cells.    

Visiting workers

Dr. Noemi Sevilla is a visitor researcher from Spain holding an OECD fellowship for 3months in the summer of 2014. She comes from Centro de Investigacion en Sanidad Animal (CISA-INIA), where she is leading a laboratory on Viral Immunology. Her research is focused on understanding the different parameters that drives the immune response against two relevant viruses on Animal Health: Bluetongue Virus (BTV) and Peste de Petits Ruminants Virus (PPRV), with the aim of improving vaccination strategies against these two viruses.

The main purpose of the project at Moredun is the study of whether the PPRV hemagglutinin (H) or whole killed PPRV activates antigen presenting cells (dendritic cells), main components of the innate immune response, via activation of Toll-like receptor (TLR) 2, or by other TLR. These data will provide relevant information on innate immune activation by PPRV.  

Outside the lab

In addition to all his work in the lab, Gary teaches on undergraduate courses at University of Edinburgh, mainly those leading to Infectious Diseases and Medical Sciences Honours Degrees.  He is also an active and enthusiastic member of the Executive Committee of Edinburgh Infectious Diseases, guiding our work with insightful comment and advice.

Gary has recently been appointed Chair of the Veterinary Immunology Committee in the  International Union of Immunological Societies (IUIS), a committee that unites the global veterinary immunology community and creates a network of expertise; and he is a member of the Advisory Board of the Veterinary Immunology Reagent Network (US-VIRN; ), a project funded by the United States Department of Agriculture to develop immunological tools to improve animal health, welfare and productivity.

In his spare time Gary is a  runner (when injury permits), cyclist, kayaker and windsurfer and can be found at the University of Edinburgh's outdoor centre at Firbush on Loch Tay, at every opportunity!

Public Engagment

Sean Wattegedera and Laura Doull also take time away from the bench to work with the Moredun Education Group.  The Group develops educational materials and exhibits that are presented various events such as the Edinburgh International Science Festival and the Royal Highland Show every year. 

Sean's invovlement with the Group is part of his role as a STEM ambassador, which sees him use his enthusiasm and commitment to encourage young people to enjoy Science, Technology, Engineering and Maths.

A selection of recent publications from Gary's group

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