Gastrointestinal nematodes are a major challenge to the UK livestock industry, and particularly to sheep farming, as a result of their impact on many aspects of animal performance (Mavrot et al, 2015). A recent estimate suggests that helminth infection costs the UK meat sheep industry £41 million annually, £15 million of which is because of the effects on production and £26 million of which is because of treatments with anthelminthic drugs (Charlier et al, 2020). Gastrointestinal nematodes also have an environmental impact, since lambs infected with gastrointestinal nematodes have higher greenhouse gas emissions than uninfected lambs (Kenyon et al, 2013; Fox et al, 2018). These impacts on economic and environmental sustainability have largely been managed with anthelmintic drugs for the past several decades, but reports of resistance to these drugs in worm populations are becoming more widespread and their efficacy is declining (Sargison et al, 2007; Rose Vineer et al, 2020). Anthelmintic residues excreted by sheep also have downstream negative effects on invertebrates, such as pollinators and dung beetles, which are essential to ecosystem health (Vokřál et al, 2023). A general reduction in anthelmintic use is therefore required, to reduce these environmental impacts and maintain refugia where susceptible gastrointestinal nematodes reside (Hodgkinson et al, 2019), increasing the lifespan of anthelmintics and ensuring they can continue to be used as part of integrated parasite management. While there is a need to reduce anthelmintic use, the publication of the Animal Health and Welfare Pathway for England (Department for Enivronment, Food and Rural Affairs, 2024) highlighted internal parasites as a priority for sheep farmers, and it is almost needless to say that their impact must be controlled. It is therefore essential to develop sustainable means of controlling gastrointestinal nematodes that do not rely heavily on anthelmintics (Jackson et al, 2009; Abbott et al, 2012; Forbes, 2023). Developing sustainable parasite control strategies is now, more than ever, an active area of research, although it is not the purpose of this article to discuss them all. Nevertheless, vaccines, grazing management and nutrition are all likely to play a role. Selective breeding to ensure that gastrointestinal nematodes have as little impact on sheep as possible has been an important tool for decades, yet has not been as widely exploited as it could be. Ultimately, breeding acts by altering the biology of the sheep, and as such it is necessary to understand the mechanisms by which sheep naturally fight infection.
Mechanisms of defence against parasites
There are two broad strategies that a host may use to manage the impacts of infection. The first, and more familiar, is resistance, which is the ability of the host to prevent infection or reduce parasite load, usually through an acquired immune response. The immune response to gastrointestinal nematodes in sheep has been well-characterised (McRae et al, 2015), and is effected through gastrointestinal nematode-specific antibodies such as IgA and IgG, which have been shown to reduce worm development, size and egg output (Aboshady et al, 2020). Resistance to gastrointestinal nematodes in sheep can be measured either through quantifying these antibodies in blood, saliva or faeces, but more practical is the measurement of worm faecal egg count: a familiar concept will be that animals with lower faecal egg count are more resistant to gastrointestinal nematodes (Figure 1A). The second, less familiar, strategy is tolerance, which is defined as the ability of a host to limit the damage caused by a given parasite burden (Råberg et al, 2009). As parasite load increases, more tolerant individuals maintain their health or performance better compared to less tolerant ones. In contrast to resistance, tolerant individuals can harbour a high parasite load but show no adverse effects on their health or performance. The mechanisms behind this are unclear in many systems, but they may prevent damage caused by infections, suppress their own damaging inflammatory responses, and/or quickly repair the damage that does occur. Measuring tolerance is more difficult than resistance, because as well as a measure of infection, some aspect of host performance must be measured, such as growth rate in lambs. The performance measure is then regressed against faecal egg count and the gradient of the slope defines the tolerance of the individual (Simms, 2000). The steeper the slope, the less tolerant an individual is (Figure 1B). While there has been some work to better understand the mechanisms underlying tolerance across a variety of host–parasite systems, they are still not well understood. Together, resistance and tolerance constitute an animal's resilience to infection, which is defined as its performance under parasite challenge (Figure 1C). Here, the level of infection does not need to be known, and resilience is defined simply by desired performance measures, and in sheep these are generally milk yield, weight or growth rate (Bisset et al, 1996a). It is important to recognise that an animal that is resilient to infection may be resistant, tolerant or both (Doeschl-Wilson et al, 2012).
Selection for defence against infection
Breeding for increased resistance to infection, largely through low worm faecal egg counts, has been studied and implemented for several decades. Faecal egg count is a heritable trait and selection of animals with low faecal egg counts results in the production of resistant lines (Bisset et al, 1996b; Morris et al, 1997). However, to develop and maintain resistance, the host must allocate a proportion of their resources into immune defence. These resources cannot then be allocated to other needs such as growth, and from the farmer's perspective, productivity. This trade-off between resistance and performance has been demonstrated in several studies showing that ‘resistant’ line lambs bred for low faecal egg counts fail to outperform their non-selected counterparts in terms of weight gain (Bisset and Morris, 1996; Greer, 2008) and a genetic trade-off between resistance and body condition (Douhard et al, 2022). A recent meta-analysis suggested that in general there is a favourable genetic relationship between resistance and productivity, such that animals that are genetically resistant are also genetically more productive (Hayward, 2022). The study also showed, however, that this depended on how resistance was selected: selection for resistant animals based on immune responses was more likely to result in a trade-off with performance (Hayward, 2022).
Such concerns have led to the idea of selecting for resilience instead, via traits such as weight gain in the absence of anthelmintic treatment or the time elapsed before a lamb requires treatment (Bisset and Morris, 1996; Bisset et al, 1996a). Resilient lines have been selected in this way, particularly in New Zealand, and have been shown to outperform resistant lines in terms of productivity without any cost in terms of increased worm faecal egg count (Morris et al, 2010). Resilience is an attractive target trait because it is defined by performance, rather than parasite burden, and is easier to measure than both resistance (which requires a faecal, blood or saliva sample and processing) and tolerance (which requires data on both faecal egg count and performance). It is, however, important to understand how resilience is underpinned by resistance and tolerance because of their differing effects on parasite epidemiology (Roy and Kirchner, 2000; Miller et al, 2005). Selection for resistance in the host imparts selection on the parasite to avoid the effects of the host immune system; what follows is a continuing ‘arms-race’ of evolution and counter-evolution that keeps parasite fecundity in check (Carval and Ferriere, 2010).
On the other hand, selection for tolerance imparts selection on the parasite to increase its fecundity, leading to the expectation of parasites that produce more eggs and hence greater pasture contamination. Both are, however, entirely theoretical expectations that are modified by factors such as the relationship between resistance and tolerance and their relative costs (Best et al, 2008; 2009), plus the input of artificial rather than natural selection. Studying both resistance and tolerance to infection is therefore important, and yet while selection for resistance and its mechanisms have been studied intensively, the same is not true of tolerance in livestock.
Breeding for tolerance
Breeding for tolerance to infection has been considered by crop breeders for over a century (Cobb, 1894) and since then it has become a key concept in plant science. Tolerance to disease, but also challenges such as temperature, drought and salinity, have been successfully selected for in may crop species (Driedonks et al, 2016; Singh et al, 2021; van den Bosch et al, 2022). Only in the 21st century has tolerance been given more attention by zo-ologists and animal geneticists, beginning with a seminal study of malaria infection in laboratory mice, which showed that tolerance to malaria varied among different mouse strains (Råberg et al, 2007). Following this, more studies have investigated tolerance in the laboratory (Lough et al, 2015; Cumnock et al, 2018) and in wild animal populations (Hayward et al, 2014; Jackson et al, 2014). Over the past decade or so, more consideration to the possibility and implications of selection for tolerance have been considered by livestock scientists (Bishop, 2012; Doeschl-Wilson and Kyriazakis, 2012; Doeschl-Wilson et al, 2012).
The first step in identifying whether selection for a trait is possible is to establish that it is heritable. Once this is established, the possibility of selection for tolerance can be raised. In a test of a vaccine for the cattle parasite Theileria parva, which causes the disease known as East Coast Fever, it was observed that nine out of 12 animals in both the vaccinated and unvaccinated groups succumbed to infection (Sitt et al, 2015). It became apparent that all three unvaccinated survivors were the offspring of a single sire, suggesting that tolerance of T. parva was inherited. A later, larger study comparing that sire's offspring, grand-offspring and unrelated animals revealed that survival was >50% in the related animals but <10% in the unrelated ones, and the related animals that did die succumbed later than unrelated animals (Latre de Late et al, 2021). In this case, tolerance was associated with a reduction in the inflammatory immune response, suggesting that control of inflammation is the main tolerance mechanism (Latre de Late et al, 2021). Tolerance to T. parva, measured as survival of infection, was subsequently found to be strongly heritable and genomic analysis found a genetic variant that almost universally survived infection (Wragg et al, 2022). While selection for tolerance to T. parva has yet to be implemented, the existence of heritable variation and genetic loci associated with tolerance, suggests that this is a possibility.
Another livestock disease where tolerance has been explored is porcine reproductive and respiratory syndrome virus (PRRSV), studies of which illustrate the difficulties of estimating genetic variance for tolerance because of amount of data required (Lough et al, 2017). Harnessing a large data set and sophisticated statistical methods did reveal genetic variation in tolerance of PRRSV and a genetic locus that contributed to this variation (Lough et al, 2018). Importantly, the genotype associated with higher tolerance was also associated with higher resistance (Lough et al, 2018), suggesting that selection for one could potentially enhance the other. This latter finding is encouraging, because mathematical simulations suggest that selection for resilience will result in beneficial effects on both resistance and tolerance if the two are positively associated (Mulder and Rashidi, 2017). Trade-offs between desirable traits is always a concern when designing selection regimes, emphasising the need to study tolerance as well as resistance.
Breeding for tolerance to gastrointestinal nematodes in live-stock has been discussed extensively (Bishop, 2012; McManus et al, 2014). Despite this interest, empirical studies of tolerance to helminths in livestock are exceedingly rare. This is potentially because tolerance is difficult to measure and it has been assumed that selection for animals that tolerate, but do not resist, gastrointestinal nematodes will increase pasture contamination (Bishop, 2012), making any animals that are not tolerant very susceptible to heavy infection. Studying tolerance is important for several reasons, however: this fear is a prediction that has yet to be empirically tested and similar fears about resilience have not been borne out (Morris et al, 2010); breeding would never be used alone and other strategies such as targeted selective treatment (Kenyon et al, 2009) could be used to complement selection for tolerance; the consequences of tolerance for resistance, resilience and animals performance are unknown. There are costs and benefits to selection for all of these traits (Table 1).
| Property | Resilience | Resistance | Tolerance |
|---|---|---|---|
| Data requirements | Low: any measure of performance or need for treatment can be used | Moderate: a faecal egg count is needed, requiring either a lab or a commercial kit | High: measures of performance and infection are needed, and some data analysis |
| Effect on pasture contamination | Early expectations are that it would increase it, but empirical evidence suggests not | Reduces it, and hence exposure to gastrointestinal nematodes for other animals | Predicted to increase it, but no empirical data |
| Consequences of selection for other traits | By definition, a resilient animal is one that performs well despite infection. Selection for resilience has been linked with improved productivity | Mixed: some studies find evidence for lower performance in Resistant animals, but others do not | Unknown: while Tolerant animals are less affected by higher parasite burdens, performance may be lower at low parasite levels. Little empirical research |
| Heritable and readily responds to selection | Yes: considerable heritability and successful selection of Resilient lines | Yes: considerable heritability and successful selection of Resistant lines | Unknown: little empirical research |
| Mechanisms understood | No: even broad conclusions such as whether Resilient animals are Resistant or Tolerant are unknown | Yes: immune response well-characterised | No: very little empirical research |
While resilience is easy to measure and positively impacts performance, its underlying mechanisms are unknown. Selection for resistance is predicted to lead to reduced pasture contamination, but may have undesirable consequences for other important traits, particularly productivity. Finally, selection for tolerance is hard to implement because of the difficulty of measuring it, but the fact that many aspects of it are unknown mean that studying it is essential.
Recently, the authors demonstrated some evidence for variation between breeds in tolerance of liver fluke infection in beef cattle (Hayward et al, 2021), although here the measure of infection was liver damage rather than fluke burden. In the last 2 years, the authors have begun empirical studies of tolerance to gastrointestinal nematodes in sheep, using controlled infection studies and field trials on both research and commercial farms. Part of this research aims to understand the relationship between tolerance and resistance to gastrointestinal nematodes by assessing how variation in immune responses is associated with these traits. For example, resistance to gastrointestinal nematodes is associated with a ‘type 2’ T-helper cell (Th2) response in sheep, but also in other mammals (Grencis, 2015; Corripio-Miyar et al, 2022), and it has also been suggested that Th2 responses could be important in tolerance of infection (Medzhitov et al, 2012). Meanwhile, inflammatory ‘type 1’ T-helper cell responses can be effective at parasite clearance, but also cause damage to the host, which may result in negative impacts (Colditz, 2008). ‘Regulatory’ T-helper cell response can help to dampen these effects and may therefore also have a role in tolerance of infection (Lopez, 2022). The authors' research is seeking to understand these associations in naturally-infected animals on a research farm. In addition, the mammalian gut is host to a complex community of commensal micro-organisms (‘gut microbiota’) that have important roles in digestion and interactions with pathogens and parasites. Recent work is showing how the gut microbiota impacts digestion efficiency in sheep (McLoughlin et al, 2020). Furthermore, selection for resistance to gastrointestinal nematodes can influence the microbiota (Castilla Gómez de Agüero et al, 2022; Paz et al, 2022), as can infection with gastrointestinal nematodes itself (Mamun et al, 2020; Corrêa et al, 2021). This research suggests that managing the ruminant microbiota could be a way of managing the impact of gastrointestinal nematodes, for example by increasing feed use efficiency, making the gut less habitable for gastrointestinal nematodes or reducing the pathological effects of gastrointestinal nematodes (Cortés et al, 2019; Cortés et al, 2020). The authors are using field trials to establish how tolerance, as well as resistance, is related to the composition of the gut microbiota. In addition, the authors are also studying how tolerance varies among animals from different genetic lines. In a study on a commercial farm in Cornwall, the authors monitored 200 weaned Romney lambs from 16 different sires across the grazing season, collecting data on body weight and gastrointestinal nematode faecal egg counts every 2 weeks. In general, higher faecal egg count was associated with lower body weight, but the authors found variation in this relationship between lambs and, crucially, between sires. These results have yet to be published in full, but show that lambs from the most tolerant sires had only around half the effect of gastrointestinal nematodes on their weight gain compared to those from the least tolerant sire. The small size of the study makes any formal genetic analysis impossible, but differences between sires point to a genetic basis for tolerance that could be exploited through breeding.
Conclusions
While breeding to reduce the impact of gastrointestinal nematodes on sheep has been implemented for decades, breeders have really only made the most of one aspect of defence against parasites in sheep, by focusing on resistance and ignoring tolerance. Livestock disease research is far behind crop science in this regard, which is partly because of the difficulty of measuring tolerance in animals, particularly in a farm setting. Nevertheless, studying tolerance of livestock disease will enable us to understand its mechanisms, its genetic basis, and its associations with other traits related to defence against infection and productivity. This may reveal ways of measuring it by proxy, or ways of promoting tolerance that could be beneficial in the fight against gastrointestinal nematodes, every tool for which is needed to take full advantage of if the goal of sustainable worm control is to be achieved.