Disentangling Genetic Variation for Resistance and Tolerance to Infectious Diseases in Animals

Hosts can in principle employ two different strategies to defend themselves against parasites: resistance and tolerance. Animals typically exhibit considerable genetic variation for resistance (the ability to limit parasite burden). However, little is known about whether animals can evolve tolerance (the ability to limit the damage caused by a given parasite burden). Using rodent malaria in laboratory mice as a model system and the statistical framework developed by plant-pathogen biologists, we demonstrated genetic variation for tolerance, as measured by the extent to which anemia and weight loss increased with increasing parasite burden. Moreover, resistance and tolerance were negatively genetically correlated. These results mean that animals, like plants, can evolve two conceptually different types of defense, a finding that has important implications for the understanding of the epidemiology and evolution of infectious diseases

CD4+T cells do not mediate within-host competition between genetically diverse malaria parasites

Ecological interactions between microparasite populations in the same host are an important source of selection on pathogen traits such as virulence and drug resistance. In the rodent malaria model Plasmodium chabaudi in laboratory mice, parasites that are more virulent can competitively suppress less virulent parasites in mixed infections. There is evidence that some of this suppression is due to immune-mediated apparent competition, where an immune response elicited by one parasite population suppress the population density of another. This raises the question whether enhanced immunity following vaccination would intensify competitive interactions, thus strengthening selection for virulence in Plasmodium populations. Using the P. chabaudi model, we studied mixed infections of virulent and avirulent genotypes in CD4+T cell-depleted mice. Enhanced efficacy of CD4+T cell-dependent responses is the aim of several candidate malaria vaccines. We hypothesized that if immune-mediated interactions were involved in competition, removal of the CD4+T cells would alleviate competitive suppression of the avirulent parasite. Instead, we found no alleviation of competition in the acute phase, and significant enhancement of competitive suppression after parasite densities had peaked. Thus, the host immune response may actually be alleviating other forms of competition, such as that over red blood cells. Our results suggest that the CD4+-dependent immune response, and mechanisms that act to enhance it such as vaccination, may not have the undesirable affect of exacerbating within-host competition and hence the strength of this source of selection for virulence

Developmental disorders among Norwegian-born children with immigrant parents

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Maximum Host Survival at Intermediate Parasite Infection Intensities

BACKGROUND: Although parasitism has been acknowledged as an important selective force in the evolution of host life histories, studies of fitness effects of parasites in wild populations have yielded mixed results. One reason for this may be that most studies only test for a linear relationship between infection intensity and host fitness. If resistance to parasites is costly, however, fitness may be reduced both for hosts with low infection intensities (cost of resistance) and high infection intensities (cost of parasitism), such that individuals with intermediate infection intensities have highest fitness. Under this scenario one would expect a non-linear relationship between infection intensity and fitness. METHODOLOGY/PRINCIPAL FINDINGS: Using data from blue tits (Cyanistes caeruleus) in southern Sweden, we investigated the relationship between the intensity of infection of its blood parasite (Haemoproteus majoris) and host survival to the following winter. Presence and intensity of parasite infections were determined by microscopy and confirmed using PCR of a 480 bp section of the cytochrome-b-gene. While a linear model suggested no relationship between parasite intensity and survival (F = 0.01, p = 0.94), a non-linear model showed a significant negative quadratic effect (quadratic parasite intensity: F = 4.65, p = 0.032; linear parasite intensity F = 4.47, p = 0.035). Visualization using the cubic spline technique showed maximum survival at intermediate parasite intensities. CONCLUSIONS/SIGNIFICANCE: Our results indicate that failing to recognize the potential for a non-linear relationship between parasite infection intensity and host fitness may lead to the potentially erroneous conclusion that the parasite is harmless to its host. Here we show that high parasite intensities indeed reduced survival, but this effect was masked by reduced survival for birds heavily suppressing their parasite intensities. Reduced survival among hosts with low parasite intensities suggests costs of controlling parasite infections; however, the nature of such costs remains to be elucidated

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 cellndashreconstituted 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

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

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Quantitative Analysis of Immune Response and Erythropoiesis during Rodent Malarial Infection

Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2–3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems

How to live with the enemy: understanding tolerance to parasites.

How do we defend ourselves against pathogenic microbes and other parasites infecting us? Research on defence against parasites has traditionally focused on resistance--the ability to prevent infection or limit parasite replication. The genetics, physiology, and evolutionary ecology of such traits are now relatively well understood. During the last few years it has been realized that another, conceptually different type of defence also plays an important role in animal host-parasite interactions. This type of defence is called tolerance, and can be defined as the ability to limit the health effects of parasites without preventing infection or controlling parasite replication. Our understanding of the causes and consequences of variation in tolerance is, however, still rudimentary. Three recent studies shed light on these questions. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness. In addition, they illustrate different approaches to untangle tolerance from other factors determining the health effects of infectious disease

Costs in the ecology and evolution of the vertebrate immune system

A central assumption of theories of the ecology and evolution of immunological defence is that defence has not only benefits (in the form of resistance against parasites), but also costs. The aim of my studies was to investigate the nature and magnitude of costs of the vertebrate immune system, and to examine some of the consequences of these costs. First, I investigated the energetic cost of the adaptive immune system. To this end, I compared the basal metabolic rate (BMR) of transgenic mice lacking an adaptive immune system (i.e. mice with only innate defence) with that of normal mice. Surprisingly, mice with only innate defence had higher BMR than normal mice. This suggests that the combination of innate and adaptive immune defence has led to energetic benefits rather than costs. Second, I examined the role of costs of defence to understand the causes and consequences of variation in immune responsiveness (IR). To this end, I used the blue tit as model organism and measured IR as the strength of the ab-response to diphtheria-tetanus (DT) vaccine. A parent-offspring analysis showed that there is a substantial amount of genetic variation in IR to at least one of the antigens. However, experimental studies also showed that IR is reduced during stress in the form of low temperature and reproductive effort, i.e. that IR is phenotypically plastic. Could this be due to an energetic trade-off between the immune response to DT and other energetically costly activities? To investigate this, I compared the BMR of immunized and control blue tits. There was no statistically significant difference in BMR between the two groups, indicating that this response is rather cheap. This makes an energetic trade-off unlikely. Instead, I have proposed that stress in the form of for example a high reproductive effort increases the risk that the immune system will attack self (immunopathology), and that the immune system is suppressed during stress to counteract that. Irrespective of whether costs of defence are expressed in the currency of energy or immunopathology, these physiological costs must translate into fitness costs to have any ecological or evolutionary consequences. To investigate if that is the case, I immunized female blue tits with DT during the nestling-feeding period and compared their level of parental effort (nestling-feeding rate) with that of control birds. Immunized birds fed their nestlings at a lower rate, indicating a potential cost of the immune response in terms of reduced fecundity. Finally, to investigate the consequences of variation in IR, I measured ab-responsiveness to DT in blue tits during winter and investigated the relationship between IR and survival to the following breeding season. Primary IR to diphtheria was subject to stabilizing selection, indicating that this component o defence has both benefits and costs. On the other hand, secondary IR to tetanus was subject to positive directional selection, which suggests that this component of defence reflects an individual’s overall condition