TY - THES

T1 - Repurposing diabetes drugs for the treatment of intestinal helminth infection

AU - Dooley, Megan

PY - 2022

Y1 - 2022

N2 - Intestinal helminth infection affects over 1.5 billion people in the most deprivedcommunities. These helminth infections cause significant morbidity, especially in children, with symptoms including malnutrition, stunted growth, and cognitive impairment. Resistance to current anthelminthic drugs is increasing, particularly in Trichuris trichiura “whipworm” infection, leading to the urgent need for new treatments. Recently, a group of immune cells at the intestinal barrier, intraepithelial lymphocytes (IELs), have been found to possess receptors for the epithelial produced peptide hormone, glucagon-like peptide-1(GLP-1). However, how these GLP-1 receptor (GLP-1r)+ IELs respond during infection is completely unknown. We used the mouse model of whipworm Trichuris muris to investigatewhether already clinically approved GLP-1r agonist treatment could influence mice chronically infected with the parasite. We utilised GLP-1r reporter, receptor null (GLP-1rKO) and immunocompromised RAG-/- mice as well as flow cytometric cytokine and epithelial pulse chase turnover experiments. We found that GLP-1r+ IELs expand at the intestinal barrier in response to chronic Trichuris infection and ex vivo treatment of GLP-1r+ IELs with GLP-1r agonists favoured a Th2/Th1 cytokine balance. In vivo treatment of alreadychronically infected mice with GLP-1r agonists significantly increased epithelial turnover, a known mechanism of intestinal parasite expulsion. Excitingly, this was coupled with rapid expulsion of the parasite, which we did not observe when treating infected GLP-1rKO or RAG-/- mice. These data suggest that GLP-1 is modulating the local intestinal immune response through GLP-1r+ IELs to induce increased epithelial turnover and expulsion of the parasite, offering an exciting potential therapeutic option for Trichuriasis. Furthermore, useof GLP-1r agonists, already approved for use in diabetics, would allow a quick and simple repurposing for treatment of these helminth infections greatly improving the quality of life of many children in developing countries.

AB - Intestinal helminth infection affects over 1.5 billion people in the most deprivedcommunities. These helminth infections cause significant morbidity, especially in children, with symptoms including malnutrition, stunted growth, and cognitive impairment. Resistance to current anthelminthic drugs is increasing, particularly in Trichuris trichiura “whipworm” infection, leading to the urgent need for new treatments. Recently, a group of immune cells at the intestinal barrier, intraepithelial lymphocytes (IELs), have been found to possess receptors for the epithelial produced peptide hormone, glucagon-like peptide-1(GLP-1). However, how these GLP-1 receptor (GLP-1r)+ IELs respond during infection is completely unknown. We used the mouse model of whipworm Trichuris muris to investigatewhether already clinically approved GLP-1r agonist treatment could influence mice chronically infected with the parasite. We utilised GLP-1r reporter, receptor null (GLP-1rKO) and immunocompromised RAG-/- mice as well as flow cytometric cytokine and epithelial pulse chase turnover experiments. We found that GLP-1r+ IELs expand at the intestinal barrier in response to chronic Trichuris infection and ex vivo treatment of GLP-1r+ IELs with GLP-1r agonists favoured a Th2/Th1 cytokine balance. In vivo treatment of alreadychronically infected mice with GLP-1r agonists significantly increased epithelial turnover, a known mechanism of intestinal parasite expulsion. Excitingly, this was coupled with rapid expulsion of the parasite, which we did not observe when treating infected GLP-1rKO or RAG-/- mice. These data suggest that GLP-1 is modulating the local intestinal immune response through GLP-1r+ IELs to induce increased epithelial turnover and expulsion of the parasite, offering an exciting potential therapeutic option for Trichuriasis. Furthermore, useof GLP-1r agonists, already approved for use in diabetics, would allow a quick and simple repurposing for treatment of these helminth infections greatly improving the quality of life of many children in developing countries.

U2 - 10.17635/lancaster/thesis/1722

DO - 10.17635/lancaster/thesis/1722

M3 - Master's Thesis

PB - Lancaster University

ER -