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Microsporidia are fungal-related obligate intracellular parasites that infect many types of animals. Microsporidia have exceptionally reduced genomes resulting in limited metabolic capabilities and are thought to be reliant on host metabolism to fuel their own growth. Here, we investigate the impact of microsporidia infection on host lipid metabolism using the nematode Caenorhabditis elegans along with its natural microsporidian pathogen Nematocida parisii . We show that infection causes an increase in the level of C. elegans lipid droplet associated lipase, ATGL-1, and a decrease in host fat levels. A mutation that decreases ATGL-1 activity and overexpression of ATGL-1 did not significantly change N. parisii infection levels. Using lipidomics we show that N. parisii infection decreases C. elegans triglyceride levels and results in increased ceramides that we speculate are synthesized by N. parisii . Mutations in host genes involved in ceramide synthesis did not significantly change the levels of N. parisii infection. Together these results show that microsporidia can cause changes to lipid metabolism of their hosts, but some individual mutations of C. elegans lipid enzymes do not alter microsporidian growth.

Microsporidia are a large phylum of intracellular parasites that can infect most types of animals. Species in the Nematocida genus can infect nematodes including Caenorhabditis elegans , which has become an important model to study mechanisms of microsporidia infection. To understand the genomic properties and evolution of nematode-infecting microsporidia, we sequenced the genomes of nine species of microsporidia, including two genera, Enteropsectra and Pancytospora , without any previously sequenced genomes. Core cellular processes, including metabolic pathways, are mostly conserved across genera of nematode-infecting microsporidia. Each species encodes unique proteins belonging to large gene families that are likely used to interact with host cells. Most strikingly, we observed one such family, NemLGF1, is present in both Nematocida and Pancytospora species, but not any other microsporidia. To understand how Nematocida phenotypic traits evolved, we measured the host range, tissue specificity, spore size, and polar tube length of several species in the genus. Our phylogenetic analysis shows that Nematocida is composed of two groups of species with distinct traits and that species with longer polar tubes infect multiple tissues. Together, our work details both genomic and trait evolution between related microsporidia species and provides a useful resource for further understanding microsporidia evolution and infection mechanisms.

Microsporidia are ubiquitous obligate intracellular pathogens of animals. These parasites often infect hosts through an oral route, but little is known about the function of host intestinal proteins that facilitate microsporidia invasion. To identify such factors necessary for infection by Nematocida parisii , a natural microsporidian pathogen of Caenorhabditis elegans , we performed a forward genetic screen to identify mutant animals that have a Fitness Advantage with Nematocida (Fawn). We isolated four fawn mutants that are resistant to Nematocida infection and contain mutations in T14E8.4 , which we renamed aaim-1 (Antibacterial and Aids invasion by Microsporidia). Expression of AAIM-1 in the intestine of aaim-1 animals restores N. parisii infectivity and this rescue of infectivity is dependent upon AAIM-1 secretion. N. parisii spores in aaim-1 animals are improperly oriented in the intestinal lumen, leading to reduced levels of parasite invasion. Conversely, aaim-1 mutants display both increased colonization and susceptibility to the bacterial pathogen Pseudomonas aeruginosa and overexpression of aaim-1 reduces P. aeruginosa colonization. Competitive fitness assays show that aaim-1 mutants are favored in the presence of N. parisii but disadvantaged on P. aeruginosa compared to wild-type animals. Together, this work demonstrates how microsporidia exploits a secreted protein to promote host invasion. Our results also suggest evolutionary trade-offs may exist to optimizing host defense against multiple classes of pathogens.

The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis -eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria. Here, the authors identify signatures of miRNA expression differentiation associated with Plasmodium falciparum infection and parasitemia in a longitudinal pediatric cohort in Burkina Faso. In particular, expression of several miRNAs known to promote lymphocyte cell death is affected during infection.

Host diversity can affect parasite prevalence, a phenomenon widely studied in macroscopic organisms. However, data from microscopic communities are lacking, despite their essential role in ecosystem functioning and the unique experimental opportunities microscopic organisms offer. Here, we study diversity–disease effects in wild nematode communities by profiting from the molecular tools available in the well-studied model nematode Caenorhabditis elegans . Nanopore sequencing was used to characterize nematode community diversity and composition, whereas parasites were identified using nine distinct experimental assays based on fluorescent staining or fluorescent reporter strains. Our results indicate that biotic stress is abundant in wild nematode communities. Moreover, in two assays, diversity–disease relations were observed: microsporidia and immune system activation were more often detected in relatively species-poor communities. Other assays, targeting different parasites, were without diversity–disease relations. Together, this study provides the first demonstration of diversity–disease effects in microbial communities and establishes the use of nematode communities as model systems to study disease–diversity relationships.

Microsporidia are a group of poorly understood, obligate intracellular eukaryotic pathogens with highly reduced genomes. They are currently a major threat to the agricultural industry and cases of fatal human infections are prevalent in immunocompromised individuals. The Nematocida parisii- Caenorhabditis elegans host pathogen model has recently been established and has provided great insight into N. parisii infection biology, but the host factors critical for infection remain poorly defined. To overcome this, we performed a forward genetic screen to isolate C. elegans mutants displaying improved fitness during N. parisii infection. I identified a host secreted protein, AAIM-1 used by N. parisii to ensure spores are oriented properly in the intestinal lumen, resulting in successful invasion. AAIM-1 plays an antibacterial role in C. elegans, protecting against the gram-negative bacterial pathogen Pseudomonas aeruginosa. Thus N. parisii utilizes a host antibacterial protein to promote its own invasion. I also screened the C. elegans microbiome “CeMbio” collection of bacteria to investigate its impact on N. parisii infection. C. scopthalmum JUb44 and S. multivorum BIGb0170 impact nematode physiology by modulating feeding behaviour, resulting in increased pharyngeal pumping and thus increased levels of N. parisii invasion. However, within 24 hours N. parisii growth is compromised. Interestingly, linoleic acid supplementation in S. multivorum BIGb0170 can restore N. parisii growth indicating its importance. I also investigated the potential for bacterial secondary products to impact dormant spores. The incubation of N. parisii spores in either Pseudomonas lurida MYb11 or Pseudomonas mendocina MSPm1 conditioned media resulted in decreased infectivity through spore destruction. In P. lurida MYb11 this was a result of the cyclic lipopeptides Massetolide E and F. Excitingly, fractionation of P. mendocina MSPm1 supernatant has revealed that two independent molecules have anti-microsporidia activity. We also demonstrate that Pseudomonas secretomes frequently contain anti-microsporidia compounds that target dormant spores. Collectively, this work identifies a host protein and dietary metabolite important for N. parisii infection. The identification of anti-microsporidia compounds represents a new and exciting avenue to identify novel therapeutic strategies by miningnaturally produced bacterial products.

Microsporidia are fungal-related obligate intracellular parasites that infect many types of animals. Microsporidia have exceptionally reduced genomes resulting in limited metabolic capabilities and are thought to be reliant on host metabolism to fuel their own growth. Here, we investigate the impact of microsporidia infection on host lipid metabolism using the nematode Caenorhabditis elegans along with its natural microsporidian pathogen Nematocida parisii. We show that infection causes an increase in the level of C. elegans lipid droplet associated lipase, ATGL-1, and a decrease in host fat levels. A mutation that decreases ATGL-1 activity and overexpression of ATGL-1 did not significantly change N. parisii infection levels. Using lipidomics we show that N. parisii infection decreases C. elegans triglyceride levels and results in increased ceramides that we speculate are synthesized by N. parisii. Mutations in host genes involved in ceramide synthesis did not significantly change the levels of N. parisii infection. Together these results show that microsporidia can cause changes to lipid metabolism of their hosts, but some individual mutations of C. elegans lipid enzymes do not alter microsporidian growth.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The author was initially entered incorrectly and has now been updated.

Microsporidia are ubiquitous obligate intracellular pathogens of animals. These parasites often infect hosts through an oral route, but little is known about the function of host intestinal proteins that facilitate microsporidia invasion. To identify such factors necessary for infection by Nematocida parisii, a natural microsporidian pathogen of Caenorhabditis elegans, we performed a forward genetic screen to identify mutant animals that have a Fitness Advantage with Nematocida (Fawn). We isolated four fawn mutants that are resistant to Nematocida infection and contain mutations in T14E8.4, which we renamed aaim-1 (Antibacterial and Aids invasion by Microsporidia). Expression of AAIM-1 in the intestine of aaim-1 animals restores N. parisii infectivity and this rescue of infectivity is dependent upon AAIM-1 secretion. N. parisii spores in aaim-1 animals are improperly oriented in the intestinal lumen, leading to reduced levels of parasite invasion. Conversely, aaim-1 mutants display both increased colonization and susceptibility to the bacterial pathogen Pseudomonas aeruginosa and overexpression ofaaim-1 reduces P. aeruginosa colonization. Competitive fitness assays show that aaim-1 mutants are favored in the presence of N. parisii but disadvantaged on P. aeruginosa compared to wild-type animals. Together, this work demonstrates how microsporidia exploits a secreted protein to promote host invasion. Our results also suggest evolutionary trade-offs may exist to optimizing host defense against multiple classes of pathogens.

Abstract Inherited immunity is an emerging field and describes how the transfer of immunity from parents to offspring can promote progeny survival in the face of infection. The mechanisms of how inherited immunity is induced are mostly unknown. The intracellular parasite Nematocida parisii is a natural microsporidian pathogen of Caenorhabditis elegans. Here, we show that N. parisii-infected worms produce primed offspring that are resistant to microsporidia infection. We find that immunity is induced in a dose dependent manner and lasts for a single generation. Intergenerational immunity prevents host cell invasion by N. parisii and also enhances survival to the bacterial pathogen Pseudomonas aeruginosa. Further, we show that inherited immunity is triggered by the host transcriptional response to infection, which can also be induced through maternal somatic depletion of negative regulators PALS-22 and the retinoblastoma protein ortholog LIN-35. We show that other biotic and abiotic stresses, such as viral infection and cadmium exposure, that induce a similar transcriptional response to microsporidia can also induce immunity in progeny. Our results demonstrate that distinct stimuli can induce inherited immunity to provide resistance against multiple classes of pathogens. These results show that activation of an innate immune response can provide protection against pathogens not only within a generation, but also in the next generation. Competing Interest Statement The authors have declared no competing interest.

Microsporidia are a large phylum of intracellular parasites that can infect most types of animals. Species in the Nematocida genus can infect nematodes including Caenorhabditis elegans, which has become an important model to study mechanisms of microsporidia infection. To understand the genomic properties and evolution of nematode-infecting microsporidia, we sequenced the genomes of nine species of microsporidia, including two genera, Enteropsectra and Pancytospora, without any previously sequenced genomes. Core cellular processes, including metabolic pathways, are mostly conserved across genera of nematode-infecting microsporidia. Each species encodes unique proteins belonging to large gene families that are likely used to interact with host cells. Most strikingly, we observed one such family, NemLGF1, is present in both Nematocida and Pancytospora species, suggesting horizontal gene transfer between species from different genera. To understand how Nematocida phenotypic traits evolved, we measured the host range, tissue specificity, spore size, and polar tube length of several species in the genus. Our phylogenetic analysis shows that Nematocida is composed of two groups of species with distinct traits and that species with longer polar tubes infect multiple tissues. Together, our work details both genomic and trait evolution between related microsporidia species and provides a useful resource for further understanding microsporidia evolution and infection mechanisms.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We have made revisions to the manuscript to improve the clarity of our study. We have also added some additional analysis in figure S12.