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

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.

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.