Haemonchus contortus is a highly pathogenic blood-feeding nematode found in the abomasum of small ruminants, that causes high morbidity and mortality worldwide, mainly in tropical and subtropical areas (Amarante, 2014). The main strategy for H. contortus and other gastrointestinal (GI) nematode control is largely based on anthelmintic treatments, however, continuous drenching has led to rapid emergence of parasite populations resistant to all commercially available anthelmintic classes (Kotze and Prichard, 2016).

Breeding for resistance against GI nematodes is a promising and sustainable strategy for parasite control in sheep, and differences between breeds regarding their resistance and susceptibility to nematode infection have been largely described (Shakya et al., 2011, Bowdridge et al., 2015, MacKinnon et al., 2015). In this context, Santa Ines sheep, a native Brazilian hair sheep widely spread all over the country, has been reported to be resistant to H. contortus infections in different age categories, including the suckling period (Amarante et al., 2004, Amarante et al., 2009, Rocha et al., 2011, Albuquerque et al., 2019, Lins et al., 2022).

During GI nematode infections, resistant breeds tend to induce an early, stronger and more effective type 2 immune response in comparison with susceptible breeds, including greater immunoglobulin production and recruitment of effector cells to the host-parasite site of interaction, which might prevent larval establishment and increase larval rejection (Inclan-Rico and Siracusa, 2018, Sorobetea et al., 2018).

Resistance to parasite infection is an inherited and polygenic trait controlled by a large number of genes with small effects, and directly involved in the immunological mechanisms that confer protection against nematodes in sheep (Benavides et al., 2016, McRae et al., 2016). Since resistance may be increased by selection of animals able to mount an effective immune response against infection, the identification of candidate genes and potential markers could improve animal selection, especially if performed during the first days of life, in order to reduce production costs (Estrada-Reyes et al., 2019).

RNA sequencing (RNA-seq) provides a single base-level precision for molecular, genetic and cellular studies (Wolf, 2013), and gene expression analyses have been applied as a promising tool for the identification of genes associated with resistance against parasitic nematodes (Guo et al., 2016, McRae et al., 2016, Zhang et al., 2019). Some candidate genes associated with sheep resistance to GI nematodes have been suggested as potential biomarkers, including SLC22A4, CXCR1, CXCR2, TLR3, CCL26 (Estrada-Reyes et al., 2019, Ahbara et al., 2021), however the molecular/cellular mechanisms driving sheep resistance remain largely unknown. Additionally, there are some classic hypotheses related to the immune-mediated mechanisms involved in sheep resistance to H. contortus infections on which we aimed to gain knowledge. Among them are the early and stronger innate cell-mediated immune response and consequently a more pronounced adaptative immune response of resistant breeds, through immunoglobulin production, and a greater tissue repair system (Albuquerque et al., 2019, Benavides et al., 2016, Lins et al., 2022).

The aim of this study was to identify gene expression signatures and physiological pathways associated with the activation and maintenance of an effective cell-mediated immune response to H. contortus of Santa Ines in comparison with Ile de France suckling lambs. Our findings are important to development of novel opportunities to enhance immunity and advance knowledge regarding breeding sheep for resistance against H. contortus.