Biology of the angiogenins and their function in gastro intestinal nematode infection

Lead Research Organisation: University of Manchester
Department Name: Life Sciences


Intestinal worms are extraordinarily common infections of domestic animals. They affect the wellbeing and productivity of livestock and thus present a large economic cost to society. Although worm infections can be cleared with drugs, animals become reinfected and many drugs are losing their effectiveness as worms develop drug resistance. Further there are consumer concerns over drug residues in meat. Thus a vaccine to protect animals from infection would be beneficial in terms of both animal welfare and the economy of the livestock industry. For most intestinal worms, we know the type of response required to control infection. Further, mechanisms are beginning to emerge relating to how the body rids itself of infection. Much of this knowledge has come from laboratory models such as whipworm infection in the mouse. Using this model we have identified an unusual family of proteins called angiogenins known to be important in defence against bacteria and which we think are also anti-parasitic. Thus these proteins are only expressed at high levels in mice able to clear the infection; mice unable to rid themselves of worms do not make these proteins. We will explore these molecules in terms of their basic biology and role in defence against worms.

Technical Summary

Mouse strains resistant to T. muris mount Th2 responses. Susceptible mice mount Th1 responses. Resistance is multifactorial, controlled mainly by IL-13 and involves innate effector mechanisms. I have identified an unusual family of antimicrobials, the angiogenins as key candidate effector molecules in worm expulsion. I now ask three urgent questions: 1. Do the angiogenins have anti-parasitic properties? 2. What are the cellular sources of angiogenins in the colon in vivo post infection? 3. What are the mechanisms which regulate angiogenin expression? These questions are important. As prevalent infections intestinal worms pose a significant economic and animal welfare problem. Gaining knowledge of the effector responses which underlie resistance to GI nematodes is prerequisite in the development of immunisation programmes. Thus we cannot design vaccines to protect against GI nematodes unless we understand the types of responses needed to protect. Further, exploring the basic biology of the angiogenins through the Th1/Th2 T. muris model will significantly extend our knowledge of immunity to mucosal infections in general. My model is powerful; a natural nematode parasite of mice. My question will be answered through a combination of in vitro and in vivo studies with functional outputs. These include (1) assessing the anti-parasitic activity of the angiogenins on larval stages of the parasite in vitro, and in vivo via treatment of normally resistant mice with an anti-angiogenin polyclonal antibody.(2) identification of the colonic sources of angiogenins in vivo using immunostaining, laser capture microdissection and global gene expression methodologies (3) analysing the influence of cytokines, parasite antigen and toll ligands on angiogenin expression in vitro using a goblet cell line/bone marrow derived macrophages and in vivo using cytokine knockout and toll receptor knock out mice.
Description 1. We identified the goblet cell as the cellular source of the anti-microbial protein angiogenin 4 in the murine large intestine.

2.We demonstrated a clear, significant correlation of angiogenin 4 production (gene expression and protein) with resistance to infection with gastro intestinal helminths and gained an understanding of how angiogenin 4 is regulated in vivo: up-regulation of angiogenin 4 is independent of IL-4 and TLR4 and dependent on IL-13.

3.We made an anti-mouse angiogenin 4 polyclonal antibody and developed its use in Immunohistochemistry, Western blotting and ELISA for quantifying angiogenin 4 production. This enabled our work to be translated into other research areas locally and abroad. (Dr Alan Pemberton - demonstrating the expression of angiogenin 4 in the small intestine post-Trichinella spiralis infection; Dr Matt Hepworth, Humboldt University of Berlin, - demonstrating the expression of angiogenin 4 in the small intestine post-Heligmosomoides bakeri infection)
Exploitation Route we made an anti-angiogenin 4 polyclonal antibody which is available for others to use
Sectors Agriculture, Food and Drink

Description Our publications have been cited by others working in the field. We have sent our anti-angiogenin 4 polyclonal antibody to other interested researchers on request.
First Year Of Impact 2009
Sector Education
Impact Types Economic

Description Public engagement: the worm wagon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact THE WORM WAGON

With other PIs within the Immunology Research group I have developed an educational public activity (the "Worm Wagon"). Our aim is to raise awareness of the global economic and health burdens imposed by gut worm infections and the role the scientist plays in studying the immune response to infection. The Worm Wagon runs annually at the University of Manchester's Science Stars event (delivering collectively to over 500 children from 10 secondary schools over 2 day) and at National Science Festivals to the general public.


With colleagues Dr JP and Dr SC and in partnership with Manchester Metropolitan University (Aarti Pandey) and a community group partner, the Inspired Sisters, based in Longsight, I was awarded a grant of £2000 funding a community project "The Art of Science: Wriggling Rangoli" as part of Manchester Science Week 2010. The aim is to increase awareness of how worm infection is one of the most significant factors that trap developing countries into poverty and how science in Manchester is helping to understand how we fight these parasites.


I am interested in engaging school children with the topic of Immunology, parasites and infection. For example we have delivered the topic of macrophage phagocytosis and antibody specificity through the medium of drama, conducting a role play with year 8 students. In 2010 we explored immunity to infection through the development of a Cluedo-style board game.I offer 4-6 week placements in my laboratory for A-level students as part of the Nuffield Bursary Scheme. Under this scheme students submit a poster for the Royal society/ British Association for the Advancement of Science CREST awards
hands-on activities, posters, leaflets, worm specimens........

no actual impacts realised to date
Year(s) Of Engagement Activity 2009