How do intestinal parasites direct the immune response?
Supervisor: Professor Simon Milling, School of Infection & Immunity
Helminth infections remain common in less-industrialised countries, where they significantly damage the health of millions of people. Conversely, their absence from industrialised countries has been associated with immune system dysregulation, leading to the ‘hygiene hypothesis’. Many socioeconomically important parasites undergo life cycle stages in the intestine, and elicit strong immune responses that attempt to control the infections. These responses are characterised primarily by Th2-type T cell responses, which produce the cytokines IL-4, IL-15 and IL-13. Beyond initiation of Th2-type T cell responses, some parasites have also been described to have immunomodulatory abilities that are not fully understood.
My lab has a long-standing interest in understanding how dendritic cells (DCs) contribute to controlling intestinal immune responses. Previous PhD students have developed tools for tracking the DCs that migrate from the intestine to the specific lymph nodes where they interact with naive T cells, and for purifying and for analysing the functions of these migratory DCs (See papers by Houston, Mayer, Andrusaite below). We are currently building on our success with bulk RNAseq and microarray analyses of migrating DCs, and have received funding to perform single cell sequencing analysis of intestinal migratory DCs. These DCs will be purified from animals after intestinal delivery of Schistosome Egg Antigen, or after infection with Heligmosomoides polygyrus, and the antigen-carrying DCs compared with DCs carrying antigen delivered in control of Th1/17-polarising conditions. This PhD will build from this work, testing hypotheses associated with understanding the signals delivered from the intestine to polarise immune responses in vivo.
The specific experiments will be designed in collaboration between the student, PI and postdoc, and will depend on the student’s specific interests.
Students undertaking this PhD or mini-project can expect to receive excellent training in understanding the immunology of the intestinal immune response at a cellular and molecular level. They will be provided opportunities to become expert in flow cytometric analysis and sorting, molecular biology (qPCR, ELISA), in analysing complex gene expression datasets (with bioinformatic support), and in working with animal models of infection.
The project will be based in the Sir Graeme Davies Building on the Gilmorehill Campus and will involve close interactions both with local groups working in mucosal Immunology and parasitology (Maizels., Maloy, and Perona-Wright), and with external collaborators, including Andrew MacDonald at the University of Manchester.
References:
Houston SA, Cerovic V, Thomson C, Brewer J, Mowat AM, Milling S. The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct. Mucosal Immunol. 2016 Mar;9(2):468-78. doi: 10.1038/mi.2015.77. Epub 2015 Sep 2. PMID: 26329428.
Mayer JU, Brown SL, MacDonald AS, Milling SW. Defined Intestinal Regions Are Drained by Specific Lymph Nodes That Mount Distinct Th1 and Th2 Responses Against Schistosoma mansoni Eggs. Front Immunol. 2020 Oct 23;11:592325. doi: 10.3389/fimmu.2020.592325. PMID: 33193437; PMCID: PMC7644866.