Insights from C. elegans into Microsporidia Biology and Host-Pathogen Relationships

Abstract

Microsporidia are poorly understood, ubiquitous eukaryotic parasites that are completely dependent on their hosts for replication. With the discovery of microsporidia species naturally infecting the genetically tractable transparent nematode C. elegans, this host has been used to explore multiple areas of microsporidia biology. Here we review results about microsporidia infections in C. elegans, which began with the discovery of the intestinal-infecting species Nematocida parisii. Recent findings include new species identification in the Nematocida genus, with more intestinal-infecting species, and also a species with broader tissue tropism, the epidermal and muscle-infecting species Nematocida displodere. This species has a longer polar tube infection apparatus, which may enable its wider tissue range. After invasion, multiple Nematocida species appear to fuse host cells, which likely promotes their dissemination within host organs. Localized proteomics identified Nematocida proteins that have direct contact with the C. elegans intestinal cytosol and nucleus, and many of these host-exposed proteins belong to expanded, species-specific gene families. On the host side, forward genetic screens have identified regulators of the Intracellular Pathogen Response (IPR), which is a transcriptional response induced by both microsporidia and the Orsay virus, which is also a natural, obligate intracellular pathogen of the C. elegans intestine. The IPR constitutes a novel immune/stress response that promotes resistance against microsporidia, virus, and heat shock. Overall, the Nematocida/C. elegans system has provided insights about strategies for microsporidia pathogenesis, as well as innate defense pathways against these parasites.

Keywords: C. elegans; Host-exposed proteins; Intracellular Pathogen Response; Microsporidia; Nematocida; Syncytium; Tissue tropism.

Fig. 5.1

Life cycle of N. parisii and N. displodere inside the C. elegans host. Longitudinal (a) and cross-sectional (b) diagrams of Nematocida infection of the C. elegans intestine, muscle, epidermis, and neurons. N. parisii spore in blue is shown in the intestinal lumen, firing a polar tube that delivers a sporoplasm (a membrane-bound parasite cell) into the cytoplasm of C. elegans intestinal cells. This sporoplasm develops in direct contact with the host cytoplasm, replicating its nuclei without undergoing cell division, to develop into a multinucleate meront. This meront can spread across intestinal cells, causing the intestinal organ to become a syncytial structure with shared cytoplasmic contents. As N. parisii meronts develop into spores, gaps appear in the terminal web (made of actin and intermediate filaments), which is thought to remove a barrier to exit. Once N. parisii meronts develop into spores, they are found in separate membrane-bound compartments of unknown origin. These spores then become coated with the small GTPase RAB-11 (in red) and fuse with the apical membrane, to be released non-lytically back into the lumen. N. displodere spore in purple is also shown in the intestinal lumen, firing a polar tube that is longer than the polar tube of N. parisii. The N. displodere polar tube is hypothesized to reach all the way from the lumen into muscle cells, epidermal cells, and neurons to deliver sporoplasms inside of these cells. N. displodere sporoplasms develop into meronts, which can lead to fusion of muscle cells to form a syncytium (the epidermis is already a syncytium). In contrast to the non-lytic exit of N. parisii, N. displodere spores appear to burst out of cells

Fig. 5.2

Model of the Intracellular Pathogen Response. Intestinal intracellular pathogens, like N. parisii and the Orsay virus, upregulate mRNA expression of a common set of C. elegans genes called the Intracellular Pathogen Response, or IPR genes. IPR genes can also be induced by proteotoxic stress, as well as by perturbation to purine metabolism. Independently of these triggers, they are also regulated by a pair of antagonistic paralogs called PALS-22 and PALS-25. Upregulation of IPR genes leads to increased resistance to pathogen infection

Fig. 5.3

Summary of pals genes. Phylogenetic tree of sequence relationships of pals genes. Green text indicates genes that are upregulated by both N. parisii and Orsay virus infection. Adapted with permission from Reddy et al. 2017