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

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.