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

肠道寄生虫可能是最重要的寄生虫，因为它们广泛流行，并通过影响动物福祉、生产力和农业，在发展中国家和发达国家（包括加拿大）产生重大的社会经济影响。更好地了解宿主-寄生虫的相互作用将导致这些寄生虫的控制策略的改进。 由杯状细胞在胃肠道中产生的粘蛋白被认为在许多寄生虫感染中对宿主具有保护作用，包括由线虫寄生虫引起的感染。胃肠道也有数万亿的肠道微生物，主要是细菌。胃肠道微生物可以通过激活不同的信号级联和分泌元件来调节粘蛋白的产生。由于线虫寄生虫和微生物在感染的胃肠道内共存，线虫和微生物群之间的相互作用很可能在杯状细胞生物学和粘蛋白产生中起重要作用。 这项研究计划的总体目标是了解肠道杯状细胞生物学和粘蛋白产生的机制与宿主-寄生虫的相互作用。建立在令人兴奋的新的初步数据，表明肠道微生物组成的改变，在小鼠感染线虫寄生虫，鞭虫，和转移的微生物群从T。在本申请中，我建议进一步探索微生物群和线虫寄生虫在杯状细胞生物学和粘蛋白产生中的相互作用。我推测线虫感染引起的肠道菌群改变调节了局部杯状细胞的反应以及粘蛋白的产生。微生物群的改变的组成与线虫一致，因此共同作用以调节与先天防御相关的杯状细胞功能。采用T.小鼠模型、GF小鼠、肠类器官和产生粘蛋白的上皮细胞系，将通过三个目标来解决该假设。 在第一个目标中，我们将确定线虫感染诱导的肠道微生物群改变在调节杯状细胞反应和粘蛋白产生与先天防御相关的作用。在第二个目标中，我们将确定Nod蛋白和TLR在线虫诱导的改变的微生物群调节粘蛋白产生中的贡献，并且在最后的目标中，我们将阐明线虫诱导的改变的微生物群调节杯状细胞反应的转录程序。 这项研究将产生关于肠道寄生虫和肠道微生物群在调节与先天防御有关的杯状细胞功能方面的相互作用的新数据。 此外，考虑到寄生虫感染在加拿大的影响，影响牲畜，伴侣动物和生态系统，这项研究将有助于了解宿主-寄生虫的相互作用，这可能最终导致改进的策略，以解决线虫寄生虫感染。

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.