Cholinergic control of innate and adaptive immunity to gastrointestinal parasites

Nematode parasites (roundworms) cause severe disease in farm animals, in particular sheep and cattle, and are responsible for significant economic losses both in the UK and worldwide. Infection is controlled by treating the animals with drugs, but the roundworms are quickly becoming resistant to all available products, a phenomenon known as multidrug resistance. Although new drugs are being developed, the likelihood is that the roundworms will develop resistance to these in turn, so there is an urgent need to develop other means of disease control in order to protect and intensify livestock production. Vaccination is the obvious alternative, but has proven difficult thus far. Immunity to roundworms is mediated by what are known as 'type 2' responses, and it is likely that anti-roundworm vaccines could be improved if we had better means to drive these. We have discovered that a signalling molecule called ACh is essential for optimal host immunity to nematode infection, and shown that a cell which is important in kick-starting type 2 responses makes this molecule. Parasites produce an enzyme to inactivate ACh, and we suggest that this is important for inhibiting host immune responses and promoting their survival. In this project, we aim to define the mechanisms whereby this signalling molecule promotes immunity to roundworms, and how the roundworms defend themselves against it. This is important for designing new strategies to improve the ability of vaccines to protect against roundworm infection.

This application aims to determine how cholinergic signalling regulates immunity to gastrointestinal nematode parasites, using acute (Nippostrongylus brasiliensis) and chronic (Heligmosomoides polygyrus) mouse models of infection. We have previously determined that cholinergic signalling through CD4+ T cells is essential for optimal host immunity to nematode infection, that pulmonary ILC2s respond to parasite infection and alarmin cytokines by synthesis and secretion of acetylcholine (ACh), and that parasite secreted acetylcholinesterase (AChE) impairs type 2 responses. These data suggest that the capacity to synthesise and release ACh is an important driver of anti-parasite immunity, and that parasite secreted AChEs evolved to regulate the host immune response. In this project, we will utilise receptor agonists, antagonists and enzymatic depletion to determine the role of ACh in priming and effector cell immunity to N. brasiliensis. In addition, we will test the significance of ILC2-derived ACh on immunity to parasite infection by using a mouse strain with cell-specific disruption of ChAT. Finally, we will utilise transcriptional silencing to determine how host and parasite AChEs contribute to regulation of host immunity. Information gained from the project should allow us to define new routes for potentiation of type 2 immunity, which can ultimately be applied to control of GI nematode infection.

Gastrointestinal nematode parasites of livestock are a growing problem both in the UK and worldwide. Low level infections contribute to poor weight gain and milk yield, whereas heavy infections have more serious consequences and can lead to death of the animal. Nematode infection of sheep has been estimated to cost the British industry over £80M/yr, and recent surveillance has highlighted a sharp increase in the incidence of helminth infection of both sheep and cattle in the UK. Resistance to anthelmintic drugs is developing rapidly, including multidrug resistance to the three major classes in current use. Vaccination is the obvious alternative control strategy, but this has proven difficult. We expect to reveal fundamental mechanisms related to initiation of type 2 responses which are critical for immunity to nematode parasites, in addition to mechanisms utilised by the parasites to suppress or modulate immunity so they can survive and cause disease in their hosts. This could ultimately be translated into better vaccine formulations for control of parasite infection of livestock in light of the progressive rise in anthelmintic resistance. The immediate aim is to make progress towards impacts on a) fundamental understanding of mechanisms of immunity and b) scientific understanding of the basis of nematode parasite persistence.

The proposal directly addresses Animal Health, a key area relating to the BBSRC strategic priorities in 'Agriculture and food security' and 'Bioscience for health'. It is aimed at development of intervention strategies for combating infectious diseases that reduce the health and welfare of livestock both in the UK and worldwide. The knowledge gained from the study will inform improved vaccine development against strongylid nematode parasites, which in turn will ultimately lead to increased economic resilience to livestock diseases and more sustainable food production. The ultimate beneficiaries of this research will therefore be farmers and those involved in the livestock industry, in addition to those outlined in 'Academic beneficiaries'.