Lars Råberg

Decomposing health: tolerance and resistance to parasites in animals.

Plant biologists have long recognized that host defence against parasites and pathogens can be divided into two conceptually different components: the ability to limit parasite burden (resistance) and the ability to limit the harm caused by a given burden (tolerance). Together these two components determine how well a host is protected against the effects of parasitism. This distinction is useful because it recognizes that hosts that are best at controlling parasite burdens are not necessarily the healthiest. Moreover, resistance and tolerance can be expected to have different effects on the epidemiology of infectious diseases and host–parasite coevolution. However, studies of defence in animals have to date focused on resistance, whereas the possibility of tolerance and its implications have been largely overlooked. The aim of our review is to (i) describe the statistical framework for analysis of tolerance developed in plant science and how this can be applied to animals, (ii) review evidence of genetic and environmental variation for tolerance in animals, and studies indicating which mechanisms could contribute to this variation, and (iii) outline avenues for future research on this topic.

On the adaptive significance of stress-induced immunosuppression

We approach the field of stress immunology from an ecological point of view and ask: why should a heavy physical workload, for example as a result of a high reproductive effort, compromise immune function? We argue that immunosuppression by neuroendocrine mechanisms, such as stress hormones, during heavy physical workload is adaptive, and consider two different ultimate explanations of such immunosuppression. First, several authors have suggested that the immune system is suppressed to reallocate resources to other metabolic demands. In our view, this hypothesis assumes that considerable amounts of energy or nutrients can be saved by suppressing the immune system; however, this assumption requires further investigation. Second, we suggest an alternative explanation based on the idea that the immune system is tightly regulated by neuroendocrine mechanisms to avoid hyperactivation and ensuing autoimmune responses. We hypothesize that the risk of autoimmune responses increases during heavy physical workload and that the immune system is suppressed to counteract this.

Animal Defenses against Infectious Agents: Is Damage Control More Important Than Pathogen Control?

The ability of hosts to withstand a given number of pathogens is a critical component of health. Now playing catch-up with plant biologists, animal biologists are starting to formally separate this form of defense from classical resistance.

The Role of Immune‐Mediated Apparent Competition in Genetically Diverse Malaria Infections

Competitive interactions between coinfecting genotypes of the same pathogen can impose selection on virulence, but the direction of this selection depends on the mechanisms behind the interactions. Here, we investigate how host immune responses contribute to competition between clones in mixed infections of the rodent malaria parasite Plasmodium chabaudi. We studied single and mixed infections of a virulent and an avirulent clone and compared the extent of competition in immunodeficient and immunocompetent mice (nude mice and T cell–reconstituted nude mice, respectively). In immunocompetent mice, the avirulent clone suffered more from competition than did the virulent clone. The competitive suppression of the avirulent clone was alleviated in immunodeficient mice. Moreover, the relative density of the avirulent clone in mixed infections was higher in immunodeficient than in immunocompetent mice. We conclude that immune‐mediated interactions contributed to competitive suppression of the avirulent clone, although other mechanisms, presumably competition for resources such as red blood cells, must also be important. Because only the avirulent clone suffered from immune‐mediated competition, this mechanism should contribute to selection for increased virulence in mixed infections in this host‐parasite system. As far as we are aware, this is the first direct experimental evidence of immune‐mediated apparent competition in any host‐parasite system.

Pheasant sexual ornaments reflect nutritional conditions during early growth

Differences in growth conditions during early life have been suggested to cause long–lasting effects on morphology and quality of adult birds. We experimentally investigated the effect of early growth conditions on the expression of sexual ornaments later in life in male ring–necked pheasants (Phasianus colchicus). We also investigated the effects on immune function, as it could be a functional link between early nutrition and ornament expression. We manipulated the dietary protein intake during the first eight weeks post hatching. Males receiving fodder with 27% protein during the first three weeks of life grew larger and more colourful wattles when sexually mature than males receiving a low–protein diet (20.5% protein). Spur length was unaffected by diet treatment. Manipulation of food protein levels during weeks 4–8 after hatching had no effect on the development of ornaments. The different protein treatments had no long–term effect on either humoral or cell–mediated immune responses. There was, however, a positive relationship between spur length and cell–mediated immune responsiveness. Our study shows that expression of a sexual ornament in adult pheasants reflects nutritional conditions early in life. Because the expression of secondary sexual ornaments is affected by conditions during early growth, by selecting more ornamented males, females would choose mates that are superior at handling early nutritional stress. If the susceptibility to early nutritional stress also has a hereditary basis, females may benefit by obtaining ‘good genes’.

The resting metabolic cost of egg laying and nestling feeding in great tits

To estimate the metabolic costs of regrowth of reproductive organs and formation of eggs, we compared the resting metabolic rate (RMR) of female great tits (Parus major) during the periods of ovarian recrudescence, egg laying, nestling feeding and during winter. We found RMR of individual females, as measured in an open circuit respirometer during night, to be significantly higher during all the breeding phases when compared to measurements during the winter. Females had a 12% increase in RMR during the nest-building phase, an increase of 27% during egg production and an increase of 20% during the chick feeding phase compared to RMR during winter. However, we found no significant difference in energy expenditure during the night between females producing eggs and females feeding chicks. A causal link between RMR and egg production was further confirmed by females producing large eggs having a higher RMR than females producing small eggs. Mass-specific RMR increased steadily from the winter throughout the breeding season, being highest when females were feeding their nestlings. Thus, even though females did not produce ovary-oviduct tissue or eggs during chick feeding, they had a very high RMR. We conclude that the biosynthetic cost of egg formation will probably not limit clutch size but may well, together with the cost of ovary-oviduct recrudescence, influence the timing of reproduction. We suggest that the high RMR of females feeding nestlings, probably is due to an increase in size and efficiency of the alimentary tract, needed to sustain a high rate of energy turnover during this period.

Resistance and tolerance in animal enemy-victim coevolution

Victim defence against enemies can be divided into resistance (minimizing successful enemy attacks) and tolerance (minimizing the fitness impact of enemy attacks). Although resistance has a negative effect on enemy fitness, tolerance, by this definition, does not necessarily; the relative importance of resistance and tolerance within a population might therefore affect enemy-victim coevolution. Resistance and tolerance have been distinguished in studies of plant defence, whereas most studies of antagonistic interactions in animals have focused on resistance, neglecting tolerance. We suggest that tolerance is also an important means of defence in animal victim-enemy interactions such as brood parasitism, mating interactions and territoriality. We discuss the potential coevolutionary consequences of tolerance variation in these animal enemy-victim interactions.

Basal metabolic rate and the evolution of the adaptive immune system

Vertebrates have evolved an adaptive immune system in addition to the ancestral innate immune system. It is often assumed that a trade–off between costs and benefits of defence governs the evolution of immunological defence, but the costs and benefits specific to the adaptive immune system are poorly known. We used genetically engineered mice lacking lymphocytes (i.e. mice without adaptive, but with innate, immunity) as a model of the ancestral state in the evolution of the vertebrate immune system. To investigate if the magnitude of adaptive defence is constrained by the energetic costs of producing lymphocytes etc., we compared the basal metabolic rate of normal and lymphocyte–deficient mice. We found that lymphocyte–deficient mice had a higher basal metabolic rate than normal mice with both innate and adaptive immune defence. This suggests that the evolution of the adaptive immune system has not been constrained by energetic costs. Rather, it should have been favoured by the energy savings associated with a combination of innate and adaptive immune defence.

NATURAL SELECTION ON IMMUNE RESPONSIVENESS IN BLUE TITS PARUS CAERULEUS

Abstract.— What is the form of natural selection on immune responsiveness? For a population at evolutionary equilibrium, there are two different scenarios. First, it is generally assumed that immune defense has both benefits and costs. If variation in immune responsiveness is due to variation in how individuals trade off these costs and benefits, one would expect immune responsiveness to be subject to stabilizing selection. Second, it is well known that an individuals immune responsiveness is often dependent on its overall condition. If immune responsiveness is condition‐dependent, one would expect immune responsiveness to be under positive directional selection. We would therefore expect that the form of natural selection on immune responsiveness depends on the relative magnitude of these two sources of variation: variation in how individuals trade off the costs and benefits of defense, and variation in condition. We measured primary and secondary antibody responsiveness to diphtheria‐tetanus vaccine in blue tits during winter and investigated the relationship between responsiveness and survival to the following breeding season. We use responsiveness to these antigens as measures of an individuals ability or propensity to mount an antibody response in case of an infection. Interestingly, different measures of responsiveness were subject to different selective regimes: primary responsiveness to diphtheria was subject to stabilizing selection, whereas secondary responsiveness to tetanus was subject to positive directional selection. In contrast, there was no significant selection on primary responsiveness to tetanus or secondary responsiveness to diphtheria. The finding of stabilizing selection on a measure of responsiveness is evidence that immune defense can incur fitness costs; a central but little‐tested assumption of theories of the ecology and evolution of immunological defense. The finding of directional selection on a measure of responsiveness is consistent with the idea that immune responsiveness is condition‐dependent, although we cannot rule out the alternative explanation that the population is not at evolutionary equilibrium with respect to this trait.

Immune responsiveness in adult blue tits: heritability and effects of nutritional status during ontogeny.

What is the relative contribution of genetic and various environmental factors to variation in the ability to mount an immune response? We measured antibody responsiveness to diphtheria-tetanus vaccine during the winter in free-ranging blue tits with a known nestling history to investigate (1) if nutritional status during the nestling stage has persistent effects on an individuals immune defence and (2) if immune responsiveness is heritable. There was no correlation between nutritional status during the nestling phase (measured as size-corrected body mass day 14 post-hatch) and antibody responsiveness as an adult. On the other hand, the heritability of responsiveness to diphtheria and tetanus, as estimated by parent-offspring regression, was 0.21±0.51 and 1.21±0.40 SE, respectively. Thus, while there was little evidence that natural variation in antibody responsiveness to these antigens reflected nutritional conditions during early life, responsiveness to at least one of the antigens (tetanus) had a strong genetic component.