The Evolution of Resistance and Tolerance to Parasites

Introduction

In the study of parasitology and disease ecology, and the ability of a host to tolerate or resist parasites has been given extra attention. First, it is important to differentiate between resistance and tolerance to apply these terms in further research. Biologists recognize that both terms refer to the ability of an organism to defend itself from harmful effects (Clarke, 1986); however, there is a difference in the way the defense mechanisms work. While resistance is the ultimate fitness of an organism to limit the burden of a parasite (Raberg, Graham, & Read, 2009), tolerance is the ability to limit the damage that may be caused by the parasite. This means that a host can be good at reducing the burden of a parasite but may not be the healthiest and thus unable to limit the damage caused by a parasite.

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Resistance Vs Tolerance

Understanding the relationship between the terms of resistance and tolerance is essential to biologists that contemplate performing manipulations of host defenses through genetic manipulations or immune interventions. For instance, if there is a negative correlation between tolerance and resistance, interventions targeted at improving resistance can negatively impact the organism’s health. From the evolutionary and ecological perspective, the differentiation between tolerance and resistance lies in the fact that resistance protects the host’s health at the parasite’s expense while tolerance saves the host’s health from harm without any negative impact on the parasite (Raberg et al., 2009). Thus, it can be suggested that there is are some differences between the ecological and evolutionary consequences of tolerance and resistance:

  1. According to Roy and Kirchner (2000), the evolution of resistance should minimize the occurrence of parasites in hosts while tolerance should have either a positive or neutral effect on the occurrence of parasites.
  2. According to Woolhouse, Webster, Domingo, Charlesworth, and Levin (2002), because resistance negatively affects the fitness of a parasite, it can impose the selection on the parasite to overcome the defense of the host. This, in turn, may lead to imposing selection for improving host resistance, causing the antagonistic relationship between the parasite and its host (Ezenwa, Archie, & White, 2016). Contrary to this, tolerance cannot hurt the parasite’s performance; thus, there is no selection on the parasite for overcoming the host’s defense. Some authors (Rausher, 2001; Boots, 2008) put forward an argument that the evolution of tolerance will not result in the open-ended antagonistic coevolution.

Therefore, because tolerance and resistance have radically opposite effects on infectious diseases and epidemiology, it is important not to confuse the two terms since it will contribute to a more in-depth understanding of the ecology and evolution of interactions between parasites and hosts.

Measuring Tolerance and Resistance

During the last decade of the twentieth century, plant biologists were successful in developing a scientific framework used for measuring resistance and tolerance. Since then, it was found that there is a presence of heritable and environmentally induced variations of both tolerance and resistance (Stowe, Marquis, Hochwender, & Simms, 2000; Kover & Schaal, 2002). Plant scientists continued to study the processes of tolerance to determine new implications for breeding plants. Nevertheless, the advancements achieved by plant scientists have had practically no impact on the innovations in the studies of animal diseases. Immunologists and parasitologists have predominantly studied the ability of hosts to prevent the burdens caused by parasites (resistance) or the overall ability to maintain health when being under threat from parasites despite the severity of the burden (combined effects of resistance and tolerance) (Medina & North, 1998). These types of measures were usually used interchangeably in the scientific literature. However, only recently, the studies of animal diseases and immunology have integrated the empirical evidence used in plant literature (Restif & Koella, 2004).

According to Simms and Triplett (1994), resistance is measured “as the inverse of infection intensity (number of parasites per host or unit host tissue); all else being equal, a lower intensity means an animal is more resistant” (p. 1979). On the other hand, tolerance is measured as the regression slope of hosts’ resistance against the intensity of the disease: the lower the slope, the higher is the tolerance (Koskela, Puustinen, Salonen, & Multikainen, 2002). Thus, a statistically correct definition of tolerance should be that is the rate of changes in fitness along with the increase of parasite burden. Ecology and evolutionary biology define this trait as a reaction norm that describes how various groups of individuals respond to specific environmental conditions (Read, 1999).

Following the explanation that tolerance is a slope, it can be stated that this trait (contrary to resistance) is impossible to measure by using one animal (Davies & Davies, 2010). Instead, resistance should be measured using a group of individuals from the same unit of hosts. Therefore, if one wishes to study the association between genetics and tolerance, it will be effective to measure the fitness of a genetically identical group of hosts that have a certain number of parasites in their systems. After measuring the fitness, it is important to compare the slopes among the different genetic units of that group (Matsumura, Arlinghaus, & Dieckmann, 2012). Genetic units may include breeds of domestic or laboratory animals or individuals that carry a specific allele at a specific locus (a gene’s position) (Raberg et al., 2009).

It is important to measure tolerance as a reaction norm because it this way, one can conclude that it is possible to observe fitness differences between types of hosts since they differ in their ability to withstand or limit the damage caused by the same parasite. If one is to measure tolerance in only one host, it may be impossible to conclude that variation between hosts originated from factors that are not associated with tolerance. To see the reason for it, let’s review the image (b) presented in Figure 1 below:

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Infection intensity.
Figure 1. Infection intensity (“Intensity of infection,” 2009).

In the figure above, the types of hosts differ in their residual deviation from a common line of regression; however, the individual lines of regression are parallel to each other. Thus, no interaction can be seen between the burden of a parasite and the type of the host. Put differently, types of hosts can vary in intercept rather than slope (Raberg et al., 2009). Because there is a constant difference in fitness across different intensiveness of an infection, it may not be associated with the mechanisms that defend from parasites. On the other hand, the difference in fitness is likely caused by the variation in the traits of hosts (Stowe et al., 2000). As mentioned by Fry (1993), other traits of hosts were given the label of “general vigor” which relates directly to the concepts of “condition” and “resource acquisition” (p. 328). The last two concepts are predominantly used by scientists operating in the sphere of animal genetics and immunology.

To rule out a specific source or variation, scientists conduct tests that determine the statistical interaction between host genotype and the burden of a parasite. For example, let’s imagine that a scientist has an aim to study the tolerance of various breeds of cattle to a specific parasite, where the interest parameter is weight gain (a production trait). It is possible that different breeds can vary in the processes of weight gain despite regardless of a parasite’s presence. Therefore, the difference in weight gain when a parasite is present can occur owing to the natural difference. It will be ineffective to compare weight gain at a specific parasite load to find out how different cattle breeds respond and tolerate the parasite. A scientist needs to answer the following question in such cases: how does the difference in weight gain among different cattle breeds change in the presence of a parasite? If a significant statistical interaction between bread and load is found, then it can be concluded that the difference in weight gain changes with parasite burden – some breeds are worse at tolerating the parasite compared to others.

The approach of “reaction-norm” is also beneficial in the sense that it allows researchers to study the relationship between an organism’s fitness and the intensity of infection. There is no a priory explanation of why such a relationship should be linear, as mentioned by Raberg et al. (2009). It is important to mention that if the relationship between fitness and the intensity of disease is non-linear, there may be drastic differences in fitness between types of hosts even in cases when there is a slight difference in the burden of a parasite (and vice versa) (Raberg et al., 2009). If to analyze the comparison of fitness and the intensity of an infection, one may get a false impression that types of hosts are different in their tolerance, while in reality they are placed at different positions along with a norm of common reactions (Kutcherov, 2016). By implementing the reaction norm approach, it will be possible to statistically control this potentially confusing factor (Henriksen, Dayton, Keyes, Carayon, & Hughes, n.d.).

Empirical Evidence

Genetic Variation

It is considered that protozoans of the Plasmodium genus are the most well-researched parasites. They cause the disease of malaria in a vast number of animals. In their study, Raberg, Sim, and Read (2007) attempted to apply a statistical framework to analyze tolerance to malaria in laboratory mice. The research used five different mice strains that had previously shown differences in resistance. To generate the variation in the intensity of infection (thus increase the statistical possibility to detect the genotype-to-burden interaction), mice were infected with one out of three clones of a parasite that differ in the severity of the infection they cause. Resistance to parasites was measured in the form of an inverse peak of parasite density. According to Mackinnon and Read (2004), the most regularly measured effects of parasite burden are anemia and weight loss, both of which are associated with animals’ mortality. Thus, Raberg et al. (2007) measured animals’ tolerance to malaria as a slope that showed a regression of anemia and weight loss against the highest density of a parasite. With regards to cases of both weight loss and anemia in mice, the regression slopes were different between strains of mice; this revealed a variation intolerance among them. Therefore, the genetic variation between different mouse strains has an impact on animals’ tolerance of the disease (Ayres & Schneider, 2008).

Environmental Variation

It can be stated that the presence of different infections simultaneously is a significant determinant of environmental variation of tolerance. Co-infecting parasites tend to affect each other in a variety of ways. According to Page, Scott, and Manabe (2006), immune-mediated interactions occur regularly and can independently impact the density of a parasite as well as the health of a host. For example, helminths often use suppressive responses to benefit their survival (Maizels et al., 2004). However, at the same time, they respond to other threats from infections by using the so-called “bystander effects” (Kamal & Khalifa, 2006). Helminths are organisms that can reduce the resistance of animals (e.g., mice) to parasites.

More importantly, an animal’s immune response to the co-infection of helminths can either increase or decrease the severity of the disease induced by a parasite without altering its density (Furze, Hussel, & Selkirk, 2006). Thus, it can be concluded that a co-infection of helminths can reduce animals’ tolerance to other parasites. Moreover, in some instances, hosts co-infected with a helminth may be at once tolerant and less resistant to other infections. For instance, helminths co-infected hosts can be less resistant to high densities of malaria but be more tolerant of immunopathological symptoms of cerebral malaria (Specht & Hoerauf, 2007). To conclude, it may be important to decide whether in the future it will be worth implementing medical interventions for promoting resistance or tolerance in animal populations infected by different parasites simultaneously (Geerts & Gryseels, 2000).

Genetic Knockouts

Some of the most valid evidence that animal organisms can defend themselves from infections not only with the help of natural resistance but also tolerance that was developed from experiments associated with genetic engineering (Whitelaw & Sang, 2005). For instance, scientists developed a species of ‘knockout mice’ in that the elimination of a specific gene lead to the altered severity of a disease without any changes in the intensity of parasites (Raberg et al., 2009). Even though such findings do not point to natural genetic variation, they show that animals can have disease control mechanisms that do more than just reduce the burden of parasites. This also points to the biological mechanisms that may reinforce an organism’s tolerance to parasites (Goldberg & Marrafini, 2015).

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Studies of knockouts have also found the existing mechanisms of tolerance in invertebrates. In their study “Identification of Drosophila mutants altering defense to and endurance of Listeria monocytogenes infection”, Ayres, Freitag, and Schneider (2008) successfully infected a thousand mutant lines of D. melanogaster (species of fly) with a bacterial pathogen Listeria monocytogenes. The study showed that 18 mutants were much more to dying from infection compared to wild types of flies. In 12 mutants, the intensity of infection elevated, which suggested that the mutants had inadequate pathways of resistance. The remaining 6 mutants were much more prone to dying from infection in cases when elevated pathogen titers were absent. Therefore, these mutants were likely to defect in the tolerance of pathways (Raberg et al., 2009). It is predicted that the tools available to scientists studying fly genetics will reveal the nature and the function of these pathways (Alberts, 2002).

Issues Related to the Evolution of Tolerance and Resistance

A popular question with regards to the evolutionary dynamics of tolerance is related to the issue of tolerance and coevolution (Raberg et al., 2009). Therefore, one of the most curious implications of tolerance is that it is much more likely to fixate as a defense mechanism rather than a resistance mechanism (Roy & Kirchner, 2000). This occurs because mechanisms of resistance usually work by eliminating parasites that favored them from the very beginning (Raberg et al., 2009). Consequently, as specific mechanisms of resistance near fixation in a certain population, parasites should change or rot off, leaving the resistance mechanism useless or unnecessary. Contrary to this, tolerance cannot minimize the selective pressure that favored parasites. Thus, it can fixate much more easily (Combes, 2000). Such insight points at an interesting possibility: are the majority of defense mechanisms occurring during evolution are equal to tolerance mechanisms (Baucom & de Roode, 2010)? It can be assumed that hosts do not get sicker from an infection because of the long succession of tolerance mechanisms that fixate in populations of organisms (Lloyd-Smith, Schreiber, Kopp, & Getz, 2005; Matthews et al., 2005).

It can be concluded that studies on tolerance should receive attention beyond the sphere of evolutionary ecology, as pointed out by researchers (Rausher, 2001; Schafer, 1971). When speaking about the context of plant diseases, the possibility of various co-evolutionary outcomes is encouraged by resistance and tolerance raising the prospect of various manipulations of host defenses that may be either proven or disproven by evolution (Horns & Hood, 2012). By not imposing the process of selection for countermeasures of pathogens, animal or public health interventions targeted at increasing tolerance may be held back by the pathogen evolution compared to those interventions that aim to boost organisms’ resistance (Mackinnon, Gandon, & Read 2008).

When exploring resistance and tolerance of organisms in the context of the agricultural sector, the attempts to make a selection for the increased yield under the threat of parasites can result in nothing (Poulin, 2010). The final issue regarding disease epidemiology is associated with the existence of “super-spreaders” – hosts responsible for developing large numbers of secondary parasite transition cases (Stein, 2011). Thus, identifying and eliminating super-spreaders has a potentially significant impact on the disease incidence rate (Blumberg, Funk, & Pulliam, 2014). About this, the following question for future research arises: are super-spreaders tolerant to parasites hosts in populations that are more resistant than others? (Rohr, Raffel, & Hall, 2010).

Conclusion

To conclude, resistance and tolerance are components of the host’s defense against parasites that differ in the way the mechanisms of defense operate. Together, the two components can give scientists an idea of how well hosts are protecting themselves from the adverse effects of parasitism processes. Distinguishing between tolerance and resistance is important for understanding that hosts that are the best at protecting themselves from the effects of parasitism are not necessarily the healthiest. Furthermore, the paper showed genetic implications for developing tolerance to parasites.

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