Modeling parasite, microbiota and host interactions to develop a better understanding of goblet cell biology

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Enteric parasites are probably the most important parasites in terms of their widespread prevalence and have major socio-economic impact in both developing and developed countries including Canada by affecting animal well--being, productivity, and agriculture. A better understanding of the host-parasite interactions will lead to improved strategies for control of these parasites. Mucins produced in the gastrointestinal (GI) tract by goblet cells are considered to have a protective role in host in a number of parasite infections, including those by nematode parasites. The GI tract also harbours trillions of commensal microbes, mainly bacteria. GI microbes can regulate mucin production by activating different signaling cascades and secretory elements. Due to the co-existence of nematode parasite and microbes within the infected GI tract, it is very likely that interactions between nematode and microbiota play an important role in goblet cell biology and mucin production. The overall objectives of this research program are to understand intestinal goblet cell biology and the mechanism of mucin production in relation to host-parasitic interactions. Built on exciting new preliminary data that shows that gut microbial composition is altered in mice infected with nematode parasite, Trichuris muris, and transfer of microbiota from T. muris-infected mice into germ free (GF) mice up-regulates goblet cells numbers, in this application, I propose to further explore the interactions between microbiota and nematode parasites in goblet cell biology and in mucin production. I hypothesize that nematode infection-induced altered gut microbiota modulates the response of local goblet cells as well as mucin production. The changed composition of the microbiota, in concert with the nematode thus acts jointly to modulate goblet cell function in relation to innate defense. By employing T. muris model, GF mice, intestinal organoids and mucin producing epithelial cell line this hypothesis will be addressed through three aims. In the first aim we will determine the role of nematode infectioninduced altered gut microbiota in regulating goblet cell responses and mucin production in relation to innate defense. In the second aim we will determine the contributions of Nod proteins and TLRs in modulation of mucin production by nematode-induced altered microbiota and in the final aim we will elucidate the transcription program by which nematode-induced altered microbiota modulates goblet cell responses. This research will generate novel data on the interactions between enteric parasite and the resident gut microbiota in modulation of goblet cell function in relation to innate defense. Furthermore, given the impact of parasite infection in Canada, affecting livestock, companion animals, and eco-systems this research will contribute in understanding host-parasite interactions which may ultimately lead to improved strategies to tackle infection with nematode parasites.