# Eprinomectin resistance in Haemonchus contortus: Phenotype, Genomic and Transcriptomic

Rémy Bétous, Robin Lioutaud, Julie Petermann, Sophie Jouffroy, Philippe Jacquiet, Fabrice Guégnard, Guillaume Sallé, Stephen R. Doyle, Anne Lespine

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Rémy Bétous, Robin Lioutaud, Julie Petermann, Sophie Jouffroy, Philippe Jacquiet, et al. Eprinomectin resistance in Haemonchus contortus: Phenotype, Genomic and Transcriptomic. Journées d'animation scientifique - Département Santé animale - INRAE, Sep 2024, Seignosse, France. hal-04700611

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Submitted on 18 Sep 2024

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# Eprinomectin Resistance in Haemonchus contortus
## Phenotype, Genomic and Transcriptomic

<figure><img src="image_1.png" /></figure>

Rémy Bétous¹, Robin Lioutaud¹, Julie Petermann², Sophie Jouffroy², Philippe Jacquiet², Fabrice Guegnard³,
Guillaume Sallé³, Steve Doyle⁴ and Anne Lespine¹

¹UMR INTHERES, ²UMR IHAP, INRAE, ENVT, Université de Toulouse, Toulouse.

³UMR ISP, INRAE, Université de Tours, Nouzilly. ⁴Wellcome Sanger Institute, Hinxton, UK

<figure><img src="image_2.png" /></figure>

France
Futur
Élevage

## INTRODUCTION

* Infections by gastrointestinal nematodes (GIN) in dairy sheep farms cause major economic losses and affect animal welfare. **Haemonchus contortus** is the most pathogenic GIN and dairy sheeps are routinely treated with **Eprinomectin** (EPR) which is the last efficient Anthelminthic with no withdrawal period.

* However, we recently reported **eprinomectin-resistant** isolates of *Haemonchus contortus* in 5 dairy sheep farms from the Pyrénées Atlantiques (Jouffroy, S. et al. *Parasitology* (2023)).

## Objectives and Originality

By **combining** farm Anthelmintic treatment history with **phenotypic**, **genomic** and **transcriptomic** data, we aim at deciphering the determinant of Eprinomectin resistance and proposing resistant markers.

<figure><img src="image_3.png" /></figure>

**location of farms** where different populations of *Haemonchus contortus* parasites were sampled

## PHENOTYPIC CHARACTERIZATION

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Resistance to EPR of field *Haemonchus contortus* populations is extremely high (>30x).

Motility of *H. contortus* larvae with increasing concentration of Eprinomectin (EPR), monitored with the WormicroTracker.

## GENOMIC COMPARISONS

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A major Quantitative Trait Locus (QTL) on chromosome V is associated to Eprinomectin resistance.

Genome-wide comparison of susceptible and Eprinomectin-resistant isolates. Pairwise genetic diversity (FST measured in 10 kbp windows using grenedalf) between one susceptible isolates (CHI) and Eprinomectin-resistant isolates (ARA, BET, BUN, MOU)

## TISSUE ENRICHMENT

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## PHENOTYPE ENRICHMENT

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Enrichment analyses highlight the potential implication of neuronal tissues such as the sensilium (Tissue enrichment), of genes responding to anthelmintics in *C. elegans* (phenotype enrichment) and in diverse cellular and metabolic functions (Gene ontology enrichment).

*C. elegans* gene orthologs significantly differentially expressed between susceptible and resistant *Haemonchus contortus* populations and with a Fold change > 1.5 were taken to perform tissue and phenotypic enrichment with Wormbase enrichment analysis tool and gene ontology enrichment with Wormcat.

## TRANSCRIPTOMIC ANALYSIS

A

<figure><img src="image_10.png" /></figure>

Gene expression is influenced by the resistance status.

Principal Component Analysis (PCA) for males and females (A), males (B) and females (C) from normalised log transformed data.

B

<figure><img src="image_11.png" /></figure>

C

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## DIFFERENTIALLY EXPRESSED GENES

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Number of differentially expressed genes between susceptible and resistant males and females and their orthologs in *C. elegans*

## GENE ONTOLOGY ENRICHMENT

<figure><img src="image_14.png" /></figure>

## CONCLUSION

Combining phenotypic, genomic and transcriptomic approaches enabled us to unveil the very high resistance to Eprinomectin of *Haemonchus contortus* isolates (>30x). These isolates selected a narrow QTL on chromosome V and genes expressed in neuronal tissues, associated with anthelmintic response and implicated in diverse cellular and metabolic functions. Investigations of individual genes deregulated and present on chromosome-V QTL are ongoing.

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RÉPUBLIQUE
FRANÇAISE

Liberté

INRAE

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Rémy Bétous, INRAE

remy.betous@inrae.fr

UMR 1436 - INTHERES

Tel. : + 33 (0)5 61 19 32 60

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32, rue Geoffroy-Saint-Hilaire, 75606 Paris Cedex 05