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

就其广泛流行而言，肠道寄生虫可能是最重要的寄生虫，并通过影响动物健康、生产力和农业，对包括加拿大在内的发展中国家和发达国家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有助于改进控制这些寄生虫的策略。在包括线虫寄生虫在内的许多寄生虫感染中，杯状细胞在胃肠道中产生的粘蛋白被认为对宿主具有保护作用。胃肠道还拥有数万亿的共生微生物，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胃肠道内共存，很可能线虫和微生物之间的相互作用在杯状细胞生物学和粘蛋白的产生中起着重要作用。本研究计划的总体目标是了解肠杯状细胞生物学和与宿主-寄生虫相互作用有关的粘蛋白产生机制。基于令人兴奋的新初步数据表明，感染了线虫寄生虫的小鼠肠道微生物组成发生了改变，并且从感染了T. muris的小鼠转移到无菌（GF）小鼠的微生物群上调了杯状细胞数量，在此应用中，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方面的相互作用。我假设线虫感染引起的肠道微生物群改变调节了局部杯状细胞的反应以及粘蛋白的产生。微生物群组成的改变，与线虫一致，共同调节杯状细胞的功能，与先天防御有关。通过小鼠模型、GF小鼠、肠道类器官和产生粘蛋白的上皮细胞系来验证这一假设。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有关的作用。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作用，在最后一个目标中，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。本研究将产生关于肠道寄生虫和常驻肠道微生物群在调节杯状细胞功能与先天防御相关的相互作用的新数据。此外，鉴于寄生虫感染对加拿大牲畜、伴侣动物和生态系统的影响，本研究将有助于了解宿主-寄生虫的相互作用，这可能最终导致解决线虫寄生虫感染的改进策略。

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 infection-induced 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.