Defining the mechanisms of mucosal defence against gastrointestinal nematodes: the role of the mucus barrier
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
Infection by gastrointestinal parasites (GI) is one of the most common types of parasitic infection in domestic livestock responsible for considerable animal ill health and economic losses for the agricultural industry. Current mechanisms of control rely on the use of chemotherapeutic approaches, which, are severely compromised in efficacy by the development of resistance by the parasite. Novel approaches to control GI helminths are needed. An understanding of host innate and adaptive defence mechanisms is key to identifying new avenues for control. Despite a considerable increase in our understanding of the immunoregulatory mechanisms that govern the adaptive immune responses to GI parasites, progress in defining the mechanisms of protection has been slow. Removal of such large multicellular pathogens from the GI tract largely revolves around the capacity of host molecules and cells to directly affect the normal metabolic activity of the parasites reducing their fitness, or indirectly alter the niche in which the parasites live making it unfavourable for parasite survival. The net result is that parasites become damaged, are not often killed by the host response but are unable to reproduce optimally and are ultimately expelled out of the host during normal intestinal transit. The mucosal barrier, comprising the intestinal epithelium and overlying mucus gel, is key site of parasite attrition.
Type 2 cytokine responses control a variety of cellular changes in the intestinal epithelia associated with host protection against GI nematodes. One important feature is goblet cell hyperplasia. Despite the fact that the major secreted factors from goblet cells are the gel-forming mucins, a clear role for these molecules in mucosal protection against GI nematodes has only recently been identified. We have identified a critical role for mucins in protective immunity to the GI nematode, Trichuris muris, a very well established in vivo model used extensively to define mechanisms of host protection. Based upon strong evidence from our earlier studies we hypothesise that gel-forming mucins are a major effector mechanism involved in protection against intestinal nematodes per se. The goals of this project are to define how gel-forming mucins mediate protection against GI nematodes using in vivo mouse models including T. muris.
Type 2 cytokine responses control a variety of cellular changes in the intestinal epithelia associated with host protection against GI nematodes. One important feature is goblet cell hyperplasia. Despite the fact that the major secreted factors from goblet cells are the gel-forming mucins, a clear role for these molecules in mucosal protection against GI nematodes has only recently been identified. We have identified a critical role for mucins in protective immunity to the GI nematode, Trichuris muris, a very well established in vivo model used extensively to define mechanisms of host protection. Based upon strong evidence from our earlier studies we hypothesise that gel-forming mucins are a major effector mechanism involved in protection against intestinal nematodes per se. The goals of this project are to define how gel-forming mucins mediate protection against GI nematodes using in vivo mouse models including T. muris.
Organisations
People |
ORCID iD |
David Thornton (Primary Supervisor) | |
Catherine Sharpe (Student) |
Publications
Bancroft AJ
(2019)
The major secreted protein of the whipworm parasite tethers to matrix and inhibits interleukin-13 function.
in Nature communications
Neill T
(2017)
Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy.
in The Journal of biological chemistry
Sharpe C
(2018)
A sticky end for gastrointestinal helminths; the role of the mucus barrier.
in Parasite immunology
Svedberg FR
(2019)
The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.
in Nature immunology
Thornton DJ
(2018)
Intracellular Processing of Human Secreted Polymeric Airway Mucins.
in Annals of the American Thoracic Society
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M011208/1 | 01/10/2015 | 31/03/2024 | |||
1618838 | Studentship | BB/M011208/1 | 01/10/2015 | 30/09/2019 | Catherine Sharpe |
Description | BSI international travel bursary |
Amount | £1,000 (GBP) |
Organisation | British Standards Institute (BSI Group) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2017 |
End | 04/2017 |
Description | Helen Muir Travel Bursary |
Amount | £750 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2017 |
End | 06/2017 |
Description | travel bursary to attend the IBCARB/BioProNet |
Amount | £250 (GBP) |
Organisation | IBCarb |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2016 |
End | 01/2016 |