High-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in <i>C. elegans</i>

Murareanu, Brandon M.; Knox, Jessica; Roy, Peter J.; Reinke, Aaron W.

doi:10.1101/2021.09.06.459184

Cited by 4 publications

(13 citation statements)

References 71 publications

(92 reference statements)

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“…The first of these to be characterized was Nematocida parisii, which naturally infects the model organism Caenorhabditis elegans 20 . This species has been used as model to understand microsporidian infection of a host, host immune responses to infection, and identify inhibitors of microsporidian infection [21][22][23][24][25][26][27][28] . Additional species that infect the intestine, N. ausubeli and N. ironsii, have also been identified 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted August 28, 2022. ; https://doi.org/10.1101/2022.08. 28.505597 doi: bioRxiv preprint infection of a host, host immune responses to infection, and identify inhibitors of microsporidian infection [21][22][23][24][25][26][27][28] . Additional species that infect the intestine, N. ausubeli and N. ironsii, have also been identified 20,21 .…”

Section: Introductionmentioning

confidence: 99%

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Genomic and phenotypic evolution of nematode-infecting microsporidia

Wadi

Jarkass

Tran

et al. 2022

Preprint

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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. Phylogenetic analysis shows that Nematocida is composed of two groups of species. 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 results demonstrate that the ability to infect multiple tissues was likely recently lost in N. homosporus and that species with longer polar tubes are able to 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic and phenotypic evolution of nematode-infecting microsporidia

Wadi

Jarkass

Tran

et al. 2022

Preprint

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“…We took advantage of the previously described phenotypes of C. elegans displaying reduced fitness when infected with N. parisii, including reduced progeny production and stunted development. 26,27,33,34 We mutagenized animals and subjected their F2 progeny to N. parisii infection. After infecting populations for five subsequent generations, we selected individual worms containing embryos, indicating increased fitness in the presence of infection (see Methods).…”

Section: Resultsmentioning

confidence: 99%

“…To identify host factors needed for infection by microsporidia, we carried out a forward genetic screen using a C. elegans model of N. parisii infection. We took advantage of the previously described phenotypes of C. elegans displaying reduced fitness when infected with N. parisii, including reduced progeny production and stunted development ( Balla et al, 2016 ; Willis et al, 2021 ; Luallen et al, 2015 ; Murareanu et al, 2021a ). We mutagenized animals and subjected their F2 progeny to N. parisii infection.…”

Section: Resultsmentioning

confidence: 99%

An intestinally secreted host factor promotes microsporidia invasion of C. elegans

Jarkass

Mok

Schertzberg

et al. 2022

eLife

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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 favoured 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.

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“…Other species of microsporidia have also been found to infect C. elegans including Pancytospora epiphaga, which is related to the human-infecting species E. bieneusi and V. cornea [40][41][42]. We recently described the use of C. elegans to screen compounds for activity towards N. parisii using a high-throughput 96-well based assay, resulting in the identification of inhibitors of microsporidia invasion and proliferation [4,37,43].…”

Section: Introductionmentioning

confidence: 99%

Screening of the Pandemic Response Box identifies anti-microsporidia compounds

Huang,

Chen,

Pan

et al. 2023

Preprint

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Microsporidia are fungi-like obligate intracellular pathogens, which infect most animals and cause microsporidiosis. Despite the serious threat that microsporidia pose to humans and agricultural animals, few drugs are available for the treatment and control of microsporidia. To identify novel inhibitors, we took advantage of the model organism Caenorhabditis elegans infected with its natural microsporidian Nematocida parisii. We used this system to screen the Pandemic Response Box, a collection of 400 diverse compounds with known antimicrobial activity. After testing these compounds in a 96-well format at high (100 μM) and low (40 μM) concentrations, we identified four inhibitors that restored the ability of C. elegans to produce progeny in the presence of N. parisii. All four compounds reduced the pathogen load of both N. parisii and Pancytospora epiphaga, a C. elegans-infecting microsporidia related to human-infecting species. One of these compounds, a known inhibitor of a viral protease, MMV1006203, inhibited invasion and prevented the firing of spores. An albendazole analog, MMV1782387, inhibited proliferation of N. parisii. We tested albendazole as well as 5 other analogs and observed that MMV1782387 was amongst the strongest inhibitors of N. parisii and displayed the least host toxicity. Our study further demonstrates the effectiveness of the C. elegans-N. parisii system for discovering microsporidia inhibitors and the compounds we identified provide potential scaffolds for anti-microsporidia drug development.

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High-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans

Cited by 4 publications

References 71 publications

Genomic and phenotypic evolution of nematode-infecting microsporidia

Genomic and phenotypic evolution of nematode-infecting microsporidia

An intestinally secreted host factor promotes microsporidia invasion of C. elegans

Screening of the Pandemic Response Box identifies anti-microsporidia compounds

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