Investigating the immunological role of intestinal mucin during steady state and acute pulmonary infection

UoM administered thesis: Phd

  • Authors:
  • Abdulelah Aljuaid

Abstract

The mucus barrier is the front line of host innate defence at mucosal surfaces, including the lung and gut. Mucins (polymeric glycoproteins) provide the structural framework of this critical barrier and are essential for its protective functions. Previous work has shown that gut parasite infection can cause local changes in the mucus barrier and can also prime mucin/mucus production at distal mucosal sites (e.g., the lung). However, how infection of the lung affects mucus production in the intestine is less well understood. The aim of the first part of the thesis was to determine whether acute pulmonary infection with influenza affected the properties and composition of the intestinal mucus barrier. When mice are intranasally infected with a sublethal dose of influenza virus, there was an increase in goblet cell numbers in the proximal colon at day 8 post-infection. Also, this was accompanied by an increase in levels of the mucin Muc-2. Interestingly, this phenotype was also observed after pulmonary bacterial infection with the pathogen Francisella tularensis. Increase in goblet cell numbers after pulmonary influenza infection was also accompanied by a change in glycosylation of their stored mucins and enhanced production of IL-13 in the colon, which has previously been shown to drive mucus production. To investigate if IL-13 plays a role in driving the goblet cell hyperplasia we saw in the proximal colon post influenza infection, we used IL-4Rα-\- knockout mice which lack a functional receptor for IL-13. In these mice, we still observed goblet cell hyperplasia after pulmonary flu infection, suggesting a dispensable role for IL-13 in this phenomenon. Thus, our results postulate a change in the intestinal mucus levels and properties after pulmonary infection, which may cause a change in the protective function of the mucus in intestine. In the other part of the thesis, we looked at the possible direct immunomodulatory function of mucins. We focussed on T cells, which have receptors for a glycans that could bind to mucin and may induce a change in the biological properties of the cells. Moreover, as intestinal T cells may become in close contact to intestinal mucus when the epithelial layer is breached, we hypothesized that interactions between T cells and mucins may regulate T cell function. To this end, intestinal mucins were purified and characterized and used to treat murine intestinal T cells. We found that intestinal T cells up-regulate an inflammatory cytokine IFN-γ when treated with intestinal mucin, but further work is needed to confirm this. Thus, defining the immunological properties of intestinal mucus during steady state or after infection will be important for understanding useful maintenance of homeostasis in the GIT.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date1 Aug 2021