2021 BBSRC-NSF/BIO: Comparative analysis of immune response programmes employed by epithelial cells to fight natural infection in C. elegans

上皮细胞在动物表面形成关键屏障，占据与感染战略相关的位置，位于内部宿主环境和外部环境之间的界面。尽管越来越多的人认识到这些细胞对所有后生动物中强大的先天免疫系统至关重要，但它们的研究不如巨噬细胞等专业免疫细胞。小线虫秀丽隐杆线虫提供了一个强大的全动物系统，在其中检查上皮细胞的免疫。C.秀丽线虫没有已知的专职免疫细胞，而是似乎严重依赖非专职免疫细胞，如上皮细胞。该模型系统的实验易处理性使得能够研究关于上皮细胞如何感知和响应病原体攻击的基本问题，以及感染期间发生的生理学相关扰动。如何C。对线虫感染的检测知之甚少。其他动物的先天免疫研究通常集中在微生物相关分子模式（MAMP）如何被感知以触发免疫反应。与此相反，C.线虫免疫已经揭示，这种宿主通常通过检测感染的影响来感知感染，称为监视免疫或效应触发免疫。C.线虫可能使用效应子触发的免疫以及MAMP触发的免疫，但对这两种免疫激活的分子机制知之甚少。此外，大多数C。elegans的研究主要集中在对细菌感染的反应上，但C.秀丽隐杆线虫可以被野生环境中的多种微生物感染，包括普遍存在的真核病原体。秀丽线虫抵抗两种不同的天然真核病原体，即微孢子虫和卵菌的感染。这些病原体代表了进化上不同的微生物谱系，微孢子虫与真菌有关，卵菌与褐藻和硅藻密切相关。这些真核病原体进化枝包括感染广泛的农业上重要的宿主的物种，包括昆虫、甲壳类动物、鱼类和植物。微孢子虫和卵菌也是普遍存在的C.线虫通过肠道（微孢子虫）或皮肤（卵菌）进入，最终传播并杀死线虫。Troemel和Barkoulas实验室的工作已经确定了防御这些不同真核病原体的共同特征，这提高了一组共同基因可能驱动肠道和皮肤上皮免疫的可能性。然而，线虫用来感知和抵抗感染的免疫防御网络的结构在很大程度上仍然是未知的。我们将采用跨病原体比较方法，以了解动物如何在正确的组织中建立适当的防御程序。剖析非专职免疫细胞对不同病原体的免疫机制是一个基本问题。在C.优雅例如，几丁质酶样蛋白已被证明可以拮抗卵菌感染的C。它们也在其他动物的炎症和疾病中发挥作用。此外，蛋白毒性应激与C.线虫，并与其他宿主的先天免疫和炎症有关。因此，这项工作将加深我们对上皮免疫的理解，并可能在水产养殖和农业中长期应用于治疗由微孢子虫和卵菌引起的许多疾病。

Epithelial cells form a critical barrier at animal surfaces, occupying positions of strategic relevance to infection being at the interface between the internal host environment and the external environment. Despite the growing appreciation of these cells as critical to a robust innate immune system in all metazoans, they are less well-studied than professional immune cells like macrophages. The small nematode Caenorhabditis elegans provides a powerful whole-animal system in which to examine immunity of epithelial cells. C. elegans does not have known professional immune cells, and instead appears to rely heavily on non-professional immune cells, such as epithelial cells. The experimental tractability of this model system enables the study of fundamental questions about how epithelial cells sense and respond to pathogen attacks, as well as the associated perturbations in physiology that occur during infection. How C. elegans detects infection is poorly understood. Innate immune studies in other animals usually focus on how microbial-associated molecular patterns (MAMPs) are sensed to trigger immune responses. In contrast, studies of C. elegans immunity have revealed that this host often senses infection through detecting the effects of infection, called surveillance immunity, or effector-triggered immunity. C. elegans likely uses effector-triggered immunity, as well as MAMP-triggered immunity, but relatively little is known about the molecular mechanisms of activation of either kind of immunity. Furthermore, most C. elegans studies have focused on response to bacterial infection, but C. elegans can be infected by diverse microbes in the wild, including ubiquitous eukaryotic pathogens.Here, we propose to study how C. elegans fights infection by two distinct clades of natural eukaryotic pathogens, namely microsporidia and oomycetes. These pathogens represent evolutionarily distinct lineages of microbes, with microsporidia being related to fungi and oomycetes being closely related to brown algae and diatoms. These eukaryotic pathogen clades include species that infect a wide range of agriculturally important hosts including insects, crustaceans, fish and plants. Microsporidia and oomycetes are also ubiquitous natural pathogens of C. elegans, entering through its intestine (microsporidia) or skin (oomycetes) to eventually spread and kill the nematodes. Work from the Troemel and Barkoulas labs has identified shared features in the defence to these diverse eukaryotic pathogens raising the possibility that a common set of genes may drive epithelial immunity in the intestine and the skin. However, it remains largely unknown what is the architecture of these immune defence networks the nematodes employ to sense and fight infection. We will pursue a cross-pathogen comparative approach to understand how the animals mount the appropriate defence programmes in the right tissues. Dissecting mechanisms of immunity in non-professional immune cells against diverse pathogens represents a fundamental problem. Various evolutionarily conserved signalling pathways and immune effectors are present in C. elegans. For example, chitinase-like proteins have been shown to antagonise oomycete infections in C. elegans and they also play a role in inflammation and disease in other animals. Furthermore, proteotoxic stress is closely linked to the immune responses against microsporidia and oomycetes in C. elegans, and is associated with innate immunity and inflammation in other hosts as well. Therefore, this work will deepen our understanding of epithelial immunity and may have long-term applications in aquaculture and agriculture to treat the many diseases caused by microsporidia and oomycetes.