Biomedical subjects

Tom J Little

Publications and source records attributed to Tom J Little.

13 recordsLinked to original sources

PubMed2006

The separate and combined effects of MHC genotype, parasite clone, and host gender on the course of malaria in mice.

BACKGROUND: The link between host MHC (major histocompatibility complex) genotype and malaria is largely based on correlative data with little or no experimental control of potential confounding factors. We used an experimental mouse model to test for main effects of MHC-haplotypes, MHC heterozygosity, and MHC x parasite clone interactions. We experimentally infected MHC-congenic mice (F2 segregants, homo- and heterozygotes, males and females) with one of two clones of Plasmodium chabaudi and recorded disease progression. RESULTS: We found that MHC haplotype and parasite clone each have a significant influence on the course of the disease, but there was no significant host genotype by parasite genotype interaction. We found no evidence for overdominance nor any other sort of heterozygote advantage or disadvantage. CONCLUSION: When tested under experimental conditions, variation in the MHC can significantly influence the course of malaria. However, MHC heterozygote advantage through overdominance or dominance of resistance cannot be assumed in the case of single-strain infections. Future studies might focus on the interaction between MHC heterozygosity and multiple-clone infections.

Animals↗

PubMed2006

Natural selection drives extremely rapid evolution in antiviral RNAi genes.

RNA interference (RNAi) is perhaps best known as a laboratory tool. However, RNAi-related pathways represent an antiviral component of innate immunity in both plants and animals. Since viruses can protect themselves by suppressing RNAi, interaction between RNA viruses and host RNAi may represent an ancient coevolutionary "arms race." This could lead to strong directional selection on RNAi genes, but to date their evolution has not been studied. By comparing DNA sequences from different species of Drosophila, we show that the rate of amino acid evolution is substantially elevated in genes related to antiviral RNAi function (Dcr2, R2D2, and Ago2). They are among the fastest evolving 3% of all Drosophila genes; they evolve significantly faster than other components of innate immunity and faster than paralogous genes that mediate "housekeeping" functions. Based on DNA polymorphism data from three species of Drosophila, McDonald-Kreitman tests showed that this rapid evolution is due to strong positive selection. Furthermore, Dcr2 and Ago2 display reduced genetic diversity, indicative of a recent selective sweep in both genes. Together, these data show rapid adaptive evolution of the antiviral RNAi pathway in Drosophila. This is a signature of host-pathogen arms races and implies that the ancient battle between RNA viruses and host antiviral RNAi genes is active and significant in shaping RNAi function.

Amino Acid Sequence↗

PubMed2006

Empirical support for optimal virulence in a castrating parasite.

The trade-off hypothesis for the evolution of virulence predicts that parasite transmission stage production and host exploitation are balanced such that lifetime transmission success (LTS) is maximised. However, the experimental evidence for this prediction is weak, mainly because LTS, which indicates parasite fitness, has been difficult to measure. For castrating parasites, this simple model has been modified to take into account that parasites convert host reproductive resources into transmission stages. Parasites that kill the host too early will hardly benefit from these resources, while postponing the killing of the host results in diminished returns. As predicted from optimality models, a parasite inducing castration should therefore castrate early, but show intermediate levels of virulence, where virulence is measured as time to host killing. We studied virulence in an experimental system where a bacterial parasite castrates its host and produces spores that are not released until after host death. This permits estimating the LTS of the parasite, which can then be related to its virulence. We exposed replicate individual Daphnia magna (Crustacea) of one host clone to the same amount of bacterial spores and followed individuals until their death. We found that the parasite shows strong variation in the time to kill its host and that transmission stage production peaks at an intermediate level of virulence. A further experiment tested for the genetic basis of variation in virulence by comparing survival curves of daphniids infected with parasite spores obtained from early killing versus late killing infections. Hosts infected with early killer spores had a significantly higher death rate as compared to those infected with late killers, indicating that variation in time to death was at least in part caused by genetic differences among parasites. We speculate that the clear peak in lifetime reproductive success at intermediate killing times may be caused by the exceptionally strong physiological trade-off between host and parasite reproduction. This is the first experimental study to demonstrate that the production of propagules is highest at intermediate levels of virulence and that parasite genetic variability is available to drive the evolution of virulence in this system.

Animals↗

PubMed2006

Parasite-host specificity: experimental studies on the basis of parasite adaptation.

Specificity in parasitic interactions can be defined by host genotypes that are resistant to only a subset of parasite genotypes and parasite genotypes that are infective on a subset of host genotypes. It is not always clear if specificity is determined by the genotypes of the interactors, or if phenotypic plasticity (sometimes called acclimation) plays a larger role. Coevolutionary outcomes critically depend on the pervasiveness of genetic interactions. We studied specificity using the bacterial parasite Pasteuria ramosa and its crustacean host Daphnia magna. First, we tested for short-term adaptation of P. ramosa lines that had been rapidly shifted among different host genotypes. Adaptation at this time-scale would demonstrate the contribution of phenotypic plasticity to specificity. We found that infectivity was stable across lines irrespective of recent passage history, indicating that in the short term infection outcomes are fixed by genetic backgrounds. Second, we studied longer-term evolution with two host clones and two parasite lines. In this experiment, P. ramosa lines had the possibility to evolve adaptations to the host genotype (clone) in which they were serially passaged, which allowed us to test for a genetic component to specificity. Substantial differences arose in the two passaged lines: one parasite line gained infectivity on the host clone it was grown on, but it lost infectivity on the other host genotype (this line evolved specificity), while the other parasite line evolved higher infectivity on both host clones. We crossed the two host genotypes used in the serial passage experiment and found evidence that the number of host genes that underlies resistance variation is small. In sum, our results show that P. ramosa specificity is a stably inherited trait, it can evolve rapidly, and it is controlled by few genes in the host. These findings are consistent with the idea of a rapid, ongoing arms race between the bacterium and its host.

Adaptation, Physiological↗

PubMed2005

The course of malaria in mice: major histocompatibility complex (MHC) effects, but no general MHC heterozygote advantage in single-strain infections.

A general MHC-heterozygote advantage in parasite-infected organisms is often assumed, although there is little experimental evidence for this. We tested the response of MHC-congenic mice (F2 segregants) to malaria and found the course of infection to be significantly influenced by MHC haplotype, parasite strain, and host gender. However, the MHC heterozygotes did worse than expected from the average response of the homozygotes.

Animals↗

PubMed2005

A parasite-mediated life-history shift in Daphnia magna.

The impact of parasitism on host populations will be modulated by both genetic variation for susceptibility, and phenotypically plastic-life-history traits that are altered to lessen the fitness consequences of infection. In this study we tested for life-history shifts in the crustacean Daphnia magna following exposure to the horizontally transmitted microsporidian, Glugoides intestinalis. In two separate experiments, we exposed hosts to parasite spores and measured their fecundity relative to controls. We show that host exposed G. intestinalis show fecundity compensation, i.e. hosts shift their life-history strategy towards early production. Our experiments included multiple host genotypes, and subtle differences among them indicated that fecundity compensation could be subject to parasite-mediated natural selection.

Analysis of Variance↗

PubMed2005

Invertebrate immunity and the limits of mechanistic immunology.

Rapid progress is being made in elucidating the molecular mechanisms involved in invertebrate immunity. This search for molecules runs the risk of missing important phenomena. In vertebrates, acquired protection and pathogen-specific responses were demonstrated experimentally long before the mechanisms responsible were elucidated. Without analogous experiments, mechanism-driven work may not demonstrate the full richness of invertebrate immunity.

Animals↗

PubMed2005

Host-parasite and genotype-by-environment interactions: temperature modifies potential for selection by a sterilizing pathogen.

Parasite-mediated selection is potentially of great importance in modulating genetic diversity. Genetic variation for resistance, the fuel for natural selection, appears to be common in host-parasite interactions, but responses to selection are rarely observed. In the present study, we tested whether environmental variation could mediate infection and determine evolutionary outcomes. Temperature was shown to dramatically alter the potential for parasite-mediated selection in two independent laboratory infection experiments at four temperatures. The bacterial parasite, Pasteuria ramosa, was extremely virulent at 20 degrees C and 25 degrees C, sterilizing its host, Daphnia magna, so that females often never produced a single brood. However, at 10 degrees C and 15 degrees C, the host-parasite interaction was much more benign, as nearly all females produced broods before becoming sterile. This association between virulence and temperature alone could stabilize coexistence and lead to the maintenance of diversity, because it would weaken parasite-mediated selection during parts of the season. Additionally, highly significant genotype-by-environment interactions were found, with changes in clone rank order for infection rates at different temperatures. Our results clearly show that the outcome of parasite-mediated selection in this system is strongly context dependent.

Animals↗

PubMed2004

Testing small clutch size models with Daphnia.

Life-history theory predicts that for small clutches, variance in egg size (between individuals) should decrease in a predictable invariant manner as clutch size increases. To test this, we studied Daphnia magna at 350 different food treatments and recorded the number of eggs and the volume of each egg for their first clutch. As predicted, we found that the relationship between clutch size and resources devoted to reproduction was linear, variance in egg volume decreased with increasing clutch size, and resources were shared relatively equally between the eggs in a clutch. However, we found that the rate at which the range of egg volumes decreased with clutch size was slower than predicted. We discuss possible explanations for this discrepancy, including a lower limit on the volume of eggs that are produced and selection for smaller eggs when food is abundant. Consistent with this, we found that mean egg volume decreased with increasing clutch size.

Animals↗

PubMed2004

Molecular evolution of daphnia immunity genes: polymorphism in a gram-negative binding protein gene and an alpha-2-macroglobulin gene.

Studies of DNA polymorphism have shown that some immune system genes of mammals and plants are exceptionally diverse, indicating that coevolution between these taxa and their parasites mediates positive selective sweeps and/or balancing selection. The genes of the arthropod immune system remain comparatively unstudied. We isolated two putative immune system genes from the cladoceran crustacean Daphnia and examined DNA sequence diversity. For one gene, encoding a putative gram-negative binding protein, we found evidence of only purifying selection, indicating that this gene is under strong functional constraint and that selection acts to eliminate amino acid variation. For another gene, encoding a putative alpha-2-macroglobulin, we found evidence of positive selection, indicating the possible involvement of this gene in a host-parasite arms race. We discuss the assumed function of these genes and offer speculation regarding which components of the arthropod immune system might experience diversifying adaptive evolution.

Amino Acid Sequence↗

PubMed2004

Ecological and evolutionary implications of immunological priming in invertebrates.

Invertebrates have an immune response that differs considerably from the acquired immune response found in vertebrates. However, new studies indicate that past experience with a pathogen can provide individual invertebrates, or their descendants, with enhanced immunity. This prophylactic effect, termed immunological priming, is functionally similar to the acquired immune response in vertebrates. This newfound complexity of invertebrate immunity begs investigation into the conditions under which immunological priming should evolve, and its consequences for population dynamics.

Journal Article↗

PubMed2004

The clearance of hidden cestode infection triggered by an independent activation of host defense in a teleost fish.

Parasites often elude effective recognition or attack (or both) by the host immune system, for example, though a tegument that possesses nonimmunogenic features. However, a general activation of host defense due to independent stimuli may increase immune activity to a level where such disguises are no longer effective, resulting in the clearance of an infection. We experimentally infected three-spined sticklebacks (Gasterosteus aculeatus) with the cestode Schistocephalus solidus. To independently foster a general immune response a few days later, we cut the tips of spines in some fish and sham-treated other fish. Cutting spines significantly reduced the prevalence of the infection. The injury evoked a physiological reaction that helped to clear a hidden parasite infection.

Analysis of Variance↗

PubMed2003

Maternal transfer of strain-specific immunity in an invertebrate.

The most celebrated component of the vertebrate immune system is the acquired response in which memory cells established during primary infection enhance the proliferation of antibodies during secondary infection. Additionally, the strength of vertebrate acquired immune responses varies dramatically depending on the infecting pathogen species or on the pathogen genotype within species. Because invertebrates lack the T-cell receptors and Major Histocompatibility Complex (MHC) molecules that mediate vertebrate adaptive immune responses, they are thought to lack adaptive immunity and be relatively unspecific in their interactions with pathogens. With only innate immunity, invertebrate hosts are believed to be nai;ve at each new encounter with pathogens. Nevertheless, some forms of facultative immunity appear to be important in insects; some individuals have enhanced immunity due to population density, and some social insects benefit when their nest-mates have been exposed to a pathogen or pathogen mimic (; see for a predation example.) Here we provide evidence for acquired strain-specific immunity in the crustacean Daphnia magna infected with the pathogenic bacteria Pasteuria ramosa. Specifically, the fitness of hosts was enhanced when challenged with a bacterial strain their mother had experienced relative to cases when mother and offspring were challenged with different strains.

Animals↗